Category Archives: Health

Study casts doubt on idea that marijuana improves sleep

Scientists say using marijuana could harm sleeping habits, according to a new study published Monday.

The study, published in the journal BMJ, showed that adults who used marijuana at least 20 times in the last month were 64 percent more likely to sleep less than six hours per night and 76 percent more likely to sleep over nine hours per night. 

It included 21,729 adults between the ages of 20 and 59, and its data, which was gathered by the National Health and Nutrition Examination Survey, is considered representative of over 146 million Americans.

“Large population-based studies show that both short sleep and long sleep are associated with an increased risk of heart attacks and strokes, as well as the long-term progression of things like atherosclerosis, diabetes, coronary artery disease and any of the major cardiovascular diseases,” the study’s lead author, Calvin Diep, said, according to CNN.

“It seems with sleep there’s kind of this ‘Goldilocks phenomenon’ where there’s an amount that ‘just right,'” Diep added.

The Centers for Disease Control and Prevention (CDC) advises that adults sleep at least seven hours a night.

Wendy Troxel, a sleep specialist and senior behavioral scientist at RAND Corporation who was not involved with the study, called this area of research “an understudied but important area, as many people are increasingly turning to cannabis products as sleep aids.” 

“But we really lack solid evidence demonstrating whether cannabis helps or hurts sleep,” Troxel added.



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L.A. County reports new omicron case, in college student returning from East Coast

Latest updates:

SAP Center announces new vaccination rules: The SAP Center announced Monday that everyone ages 3-11 now has to be fully vaccinated or show proof of a negative coronavirus test within the past 72 hours to enter the venue. The policy, effective this Thursday with the Sharks game against the Minnesota Wild, is in keeping with the state and San Jose guidelines for mega-events, such as concerts and sporting events, Sharks Sports & Entertainment said. Everyone 12 and older already has to show proof of full vaccination. The policy for kids 11 and under will not be in effect for Tuesday’s game against the Calgary Flames. Details are here.

CDC underscores holiday testing and quarantine rules for air travel: The Centers for Disease Control and Prevention on Monday re-emphasized, amid concerns over the new omicron coronavirus variant, that international travelers arriving in the United States now must be tested for the coronavirus no more than one day before they travel and show proof of negative results to the airline. CDC recommends also that international travelers get a COVID-19 test 3-5 days after arrival, and that unvaccinated travelers quarantine for seven days after travel.

Pandemic stress hits young hardest: A new poll finds that teens and young adults have faced some of the heaviest pandemic-era stress as they come of age during a time of extreme turmoil. Overall, more than a third of Americans ages 13 to 56 cite the pandemic as a major source of stress, and many say it has made certain parts of their lives harder, according to a new survey from MTV Entertainment Group and The Associated Press-NORC Center for Public Affairs Research. But when it comes to education, friendships and dating, the disruption has had a pronounced impact among Generation Z, ages 13 to 24. Of that group, 46% said the pandemic has made it harder to pursue their education or career goals, compared with 36% of Millennials and 31% in Generation X. There was a similar gap when it came to dating and romantic relationships, with 40% of Gen Z saying it became harder.

Another omicron case in L.A. County: The Los Angeles County health department on Monday announced confirmation of a new coronavirus case involving the omicron variant. The variant was found in a fully vaccinated college student who returned to the county after travel on the East Coast. The person had mild symptoms and is self-isolating, county officials said. “Public Health has identified close contacts in Los Angeles County, all of whom are quarantining and being tested,” the department said. “Based on travel history, it is likely that the infection was acquired outside of Los Angeles County.” The county also reported an omicron infection case last week, saying it too was likely related to travel, in that case to South Africa where the omicron variant first emerged.

Has the pandemic put college further out of reach for Californians?: Enrollment in California community colleges declined by nearly 15% last year. As colleges of all kinds grapple with how to come back from a pandemic that deepened existing educational inequities, some students are wondering if they can. Read the full story here.

New York City mayor announces vax mandates for private sector employers: New York City Mayor Bill de Blasio announced Monday that private employers will have to mandate COVID-19 vaccinations for their employees. During an appearance on MSNBC, de Blasio called the move a “preemptive strike” in the face of the omicron variant and the coming winter season.

Early reports on new variant encouraging, Fauci says: Despite the rapid spread of the omicron coronavirus through the U.S., federal health officials say early signs indicate it may not be as dangerous as the dominant delta variant, which is responsible for a rise in hospitalizations. Top White House infectious disease adviser Dr. Anthony Fauci told CNN’s “State of the Union” Sunday that hospitalization rates in South Africa, where omicron emerged and is becoming the dominant strain, have not increased to concerning levels. “Thus far, it does not look like there’s a great degree of severity to it,” Fauci said, according to the Associated Press. “But we have really got to be careful before we make any determinations that it is less severe or it really doesn’t cause any severe illness, comparable to delta.” Fauci said the Biden administration is considering lifting the travel restrictions on several African countries imposed when omicron spread rapidly across the region.

Should we change up our masks? Although Bay Area counties so far have not signaled any changes in their mask policies, the arrival of the omicron variant has many people wondering whether it’s time to double down on their masking habits — and upgrade their face coverings. Read what Bay Area experts advise on how to protect yourself here.

Tear gas used to disperse Belgian protest against restrictions: Belgian police used water cannon and tear gas Sunday to disperse some rowdy protesters in Brussels after thousands marched mostly peacefully to protest tightened COVID-19 restrictions against a surge of coronavirus infections. Some demonstrators were reported to throw stones at police and attempt to dismantle barricades. Demonstrators rejected new measures announced Friday, the third week in a row that the government has tightened its rules as an avalanche of new cases strains the country’s health services, depriving people with other life-threatening diseases of treatment. Shouting “Freedom! Freedom!” some marchers carried signs critical of vaccines and against making vaccine shots mandatory.

Marin school sees COVID-19 outbreak after parents sent sick child to class: Corte Madera school officials have vowed to take “corrective action” after the parents of an elementary school student knowingly sent the child and a sibling to class despite the child’s having tested positive for COVID-19, spurring a spate of other infections. As of Friday, school officials said eight children at Neil Cummins Elementary School had contracted the virus and 75 had been quarantined since the family, which has not been identified, allowed its two kids to attend school even after being notified by public health officials the week of Nov. 8 that one of the children was infected. The sibling later tested positive as well, the AP reported. Read the full story.

J&J booster appears fine for Pfizer vaccine recipients, study finds: People who received Pfizer vaccines against the coronavirus may get as much benefit from a Johnson & Johnson booster shot as a Pfizer one, according to a small study released on Sunday. The study, which is not yet peer-reviewed, from Beth Israel Deaconess Medical Center in Boston looked at 65 people fully vaccinated with Pfizer-BioNtech’s two-dose vaccine. For booster shots, 24 were given the Pfizer vaccine and 41 got a Johnson & Johnson shot. Both groups experienced a boost in COVID-fighting T-cells. But the T-cell increase from the Johnson & Johnson vaccine was significantly higher than Pfizer’s. “The durability of these immune responses remains to be determined,” the authors wrote.

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Study: Test detects signs of dementia at least six months earlier than standard method

A study released Monday concluded that a self-administered test detected signs of potential dementia, including Alzheimer’s disease, at least six months ahead of the standard testing method, suggesting the exam may help doctors diagnose patients sooner. 

The self-administered gerocognitive examination (SAGE) test picked up on signs of cognitive impairment months earlier among patients than the often used mini-mental state examination (MMSE), according to the research published in the journal “Alzheimer’s Research & Therapy.” 

The study involved more than 600 participants who visited the Ohio State University’s Center for Cognitive and Memory Disorders over eight years, who had at least two visits six months apart and who took both the SAGE and MMSE tests. 

Among those who developed dementia during the study period, researchers determined that the first “significant decline” in SAGE scores occurred in an average 14.4 months after first taking the tests. 

MMSE scores, on the other hand, for those eventually diagnosed with Alzheimer’s saw the first “significant decline” at an average of 20.4 months since the initial tests. Among those later diagnosed with another form of dementia, the standard test detected the decline at an average of 32.9 months after the first tests.

Those who had Alzheimer’s when they took the first tests saw their first major decline about 8.3 months from the initial SAGE test, compared to 14.4 months for MMSE results. 

Lead author Douglas Scharre, the director of the division of cognitive neurology at Ohio State University, told The Hill that he helped develop the SAGE test due to his “frustration” when patients came in with a condition that had worsened in recent years. 

“They were just coming in too late, and I figured we needed something better, something that was accurate but more practical,” Scharre said. “And so the way to do that is self-administered.”

“By the time it’s obvious to everyone they’ve usually progressed further than we want,” he added. “And so now that we have potential disease modifying treatments that are actually available, the need to identify people earlier is really critical.”

The SAGE test intends to track the patients’ thinking processes and to spot cognitive impairment symptoms beyond normal aging. 

But the exam itself is not diagnostic and cannot determine whether a patient has Alzheimer’s or another form of dementia, and scientists recommend patients take the test into their doctors’ office for analysis. 

Patients who develop mild cognitive impairment do not automatically develop Alzheimer’s or another type of dementia. 

The SAGE test would signal “significant” cognitive decline if a patient’s score falls two or three points within about 12 to 18 months, Scharre said. 

As a self-administered test, the SAGE test can be taken in any location, including at home or in waiting rooms, and therefore, does not take up physicians’ time. 

The paper version of the SAGE test is free. The digital version is available through BrainTest. 

Research on the SAGE test comes after the Food and Drug Administration (FDA) authorized the first Alzheimer’s drug in almost 20 years in a controversial decision. Biogen’s drug Aduhelm is designed for those with mild cognitive impairment. 

But the FDA’s decision has come under scrutiny with two House committees investigating the authorization that came after an advisory panel unanimously opposed the drug. 

Aduhelm, priced at $56,000 per year, is also linked in part to an expected increase in Medicare premiums for 2022. In response, Sen. Bernie SandersBernie SandersWTO faces renewed scrutiny amid omicron threat Overnight Health Care — Presented by March of Dimes — Abortion access for 65M women at stake Hospitals in underserved communities face huge cuts in reckless ‘Build Back Better’ plan MORE (I-Vt.) called on President BidenJoe BidenChina eyes military base on Africa’s Atlantic coast: report Biden orders flags be flown at half-staff through Dec. 9 to honor Dole Biden heading to Kansas City to promote infrastructure package MORE last week to delay Medicare’s approval for use for Aduhelm.



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Immunogenicity, safety, and reactogenicity of heterologous COVID-19 primary vaccination incorporating mRNA, viral-vector, and protein-adjuvant vaccines in the UK (Com-COV2): a single-blind, randomised, phase 2, non-inferiority trial

Summary

Background

Given the importance of flexible use of different COVID-19 vaccines within the same schedule to facilitate rapid deployment, we studied mixed priming schedules incorporating an adenoviral-vectored vaccine (ChAdOx1 nCoV-19 [ChAd], AstraZeneca), two mRNA vaccines (BNT162b2 [BNT], Pfizer–BioNTech, and mRNA-1273 [m1273], Moderna) and a nanoparticle vaccine containing SARS-CoV-2 spike glycoprotein and Matrix-M adjuvant (NVX-CoV2373 [NVX], Novavax).

Methods

Com-COV2 is a single-blind, randomised, non-inferiority trial in which adults aged 50 years and older, previously immunised with a single dose of ChAd or BNT in the community, were randomly assigned (in random blocks of three and six) within these cohorts in a 1:1:1 ratio to receive a second dose intramuscularly (8–12 weeks after the first dose) with the homologous vaccine, m1273, or NVX. The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG concentrations measured by ELISA in heterologous versus homologous schedules at 28 days after the second dose, with a non-inferiority criterion of the GMR above 0·63 for the one-sided 98·75% CI. The primary analysis was on the per-protocol population, who were seronegative at baseline. Safety analyses were done for all participants who received a dose of study vaccine. The trial is registered with ISRCTN, number 27841311.

Findings

Between April 19 and May 14, 2021, 1072 participants were enrolled at a median of 9·4 weeks after receipt of a single dose of ChAd (n=540, 47% female) or BNT (n=532, 40% female). In ChAd-primed participants, geometric mean concentration (GMC) 28 days after a boost of SARS-CoV-2 anti-spike IgG in recipients of ChAd/m1273 (20 114 ELISA laboratory units [ELU]/mL [95% CI 18 160 to 22 279]) and ChAd/NVX (5597 ELU/mL [4756 to 6586]) was non-inferior to that of ChAd/ChAd recipients (1971 ELU/mL [1718 to 2262]) with a GMR of 10·2 (one-sided 98·75% CI 8·4 to ∞) for ChAd/m1273 and 2·8 (2·2 to ∞) for ChAd/NVX, compared with ChAd/ChAd. In BNT-primed participants, non-inferiority was shown for BNT/m1273 (GMC 22 978 ELU/mL [95% CI 20 597 to 25 636]) but not for BNT/NVX (8874 ELU/mL [7391 to 10 654]), compared with BNT/BNT (16 929 ELU/mL [15 025 to 19 075]) with a GMR of 1·3 (one-sided 98·75% CI 1·1 to ∞) for BNT/m1273 and 0·5 (0·4 to ∞) for BNT/NVX, compared with BNT/BNT; however, NVX still induced an 18-fold rise in GMC 28 days after vaccination. There were 15 serious adverse events, none considered related to immunisation.

Interpretation

Heterologous second dosing with m1273, but not NVX, increased transient systemic reactogenicity compared with homologous schedules. Multiple vaccines are appropriate to complete primary immunisation following priming with BNT or ChAd, facilitating rapid vaccine deployment globally and supporting recognition of such schedules for vaccine certification.

Funding

UK Vaccine Task Force, Coalition for Epidemic Preparedness Innovations (CEPI), and National Institute for Health Research. NVX vaccine was supplied for use in the trial by Novavax.

Introduction

The COVID-19 pandemic that began in 2019 has resulted in more than 5 million deaths to date.
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Our world in data. Statistics and research coronavirus pandemic (COVID-19). https://doi.org/10/2021 2021. https://ourworldindata.org/coronavirus (accessed Nov 30, 2021).

As of Oct 20, 2021, over 3 billion people globally have received at least one dose of a SARS-COV-2 vaccine, but only 2·8% of people in low-income countries.

1

Our world in data. Statistics and research coronavirus pandemic (COVID-19). https://doi.org/10/2021 2021. https://ourworldindata.org/coronavirus (accessed Nov 30, 2021).

Although there are now 24 different vaccines approved worldwide, manufacturing issues, raw material shortages, and surges in infection have led to supply chain disruption and delays.

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  • Li X
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Mathematical model of the feedback between global supply chain disruption and COVID-19 dynamics.

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India’s COVID-vaccine woes—by the numbers.

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UNICEF
COVID-19 Vaccine Market Dashboard.

The emergence of new safety concerns with available vaccines led to changes in vaccine deployment policy. In early 2021, multiple countries implemented age restrictions for the ChAdOx1 n-CoV-19 vaccine (AstraZeneca, hereafter referred to as ChAd) after the emergence of vaccine-induced thrombocytopenia and thrombosis, and recent pauses in immunisation of young people with mRNA vaccines due to concerns about myocarditis.

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Covid-19: Sweden, Norway, and Finland suspend use of Moderna vaccine in young people “as a precaution”.

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European Medicines Agency
AstraZeneca’s COVID-19 vaccine: EMA finds possible link to very rare cases of unusual blood clots with low blood platelets.

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Department of Health and Social Care
Use of the AstraZeneca COVID-19 (AZD1222) vaccine: updated JCVI statement.

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  • Liu X
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  • et al.
Safety and immunogenicity of heterologous versus homologous prime-boost schedules with an adenoviral vectored and mRNA COVID-19 vaccine (Com-COV): a single-blind, randomised, non-inferiority trial.

Such changes have disrupted roll-out plans, and have the potential to do so in future. Additionally, concerns about waning vaccine immunity, and the potential for existing schedules to protect against new SARS-CoV-2 variants of concern have led to questions on the optimisation of vaccine schedules.

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  • Cevik M
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COVID-19 vaccines: keeping pace with SARS-CoV-2 variants.

Research in context

Evidence before this study

Most high-income countries have now vaccinated their adult populations with a primary course of COVID-19 vaccine, but deployment remains low across lower income regions. Heterologous prime-boost schedules are a measure that could enhance deployment flexibility and improve access to vaccines. Evidence to support the use of mixed schedules is rapidly evolving. We searched PubMed for articles published between database inception and Oct 20, 2021 using the terms “(COVID) AND (heterologous) AND (vaccin*) NOT (BCG)” with no language restrictions. An additional search was done of the medRxiv preprint server. There are few randomised controlled trials examining heterologous schedules, but many observational studies. Heterologous schedules studied included: ChAdOx1 nCoV-19 (ChAd)/BNT162b2 (BNT), BNT/ChAd, ChAd/mRNA-1273, Ad26/Ad5, ChAd/BBV152, Coronavac/ChAd, Coronavac/Convidecia, and Ad26/BNT. Where a homologous comparator was included, reactogenicity appeared increased in heterologous boost, but was tolerated. There were no safety concerns identified in any study. Heterologous schedules were immunogenic, with mRNA boost after ChAd prime inducing higher concentrations of neutralising antibodies when compared with homologous ChAd. mRNA boost after ChAd prime induced a T-cell response above that of homologous comparators. Adenoviral-vectored boost after inactivated prime appears to enhance immunogenicity over that of inactivated prime-boost.

Added value of this study

These data are the first from a randomised controlled trial of COVID-19 vaccines of heterologous mRNA boost and protein-subunit boost. We have shown that reactogenicity at boost is consistently increased in heterologous versus homologous schedules of ChAd and mRNA vaccines, but not increased by NVX-CoV2373 (NVX) boost after ChAd or BNT prime. mRNA-1273 as a heterologous boost after ChAd or BNT prime induces a higher binding and neutralising antibody response than either homologous schedule. Heterologous boost with NVX after ChAd prime was superior to homologous ChAd for induction of humoral and cellular immunity. NVX after BNT prime did not meet non-inferiority criteria for binding antibodies when compared with homologous BNT; however, in a non-randomised comparison, binding antibody concentrations were still well above the geometric mean concentration observed following ChAd/ChAd. Decrements in neutralising antibody responses to beta and delta variants of concern were largely conserved across schedules, whereas T-cell responses were not affected.

Implications of all the available evidence

This study adds to the body of evidence that heterologous COVID-19 vaccination is safe, tolerated, and immunogenic. Flexibility of schedules should be considered to improve access to COVID-19 vaccination globally.

Heterologous prime-boost COVID-19 vaccination might be useful in responding to these challenges. Many national immunisation advisory groups implemented this strategy on a pragmatic basis following ChAd-related vaccine-induced thrombocytopenia and thrombosis events before evidence had accrued.
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Danish Health Authority
Denmark continues its vaccine rollout without the COVID-19 vaccine from AstraZeneca.

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Public Health Agency of Canada
Recommendations on the use of COVID-19 vaccines.

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Haute Autorite de Sante
Vaccins contre la Covid-19 : la HAS maintient la limite d’âge de 55 ans pour Vaxzevria. 12/05/2021.

Since then, a number of studies have shown an acceptable short-term safety profile of ChAd and BNT162b2 (Pfizer–BioNTech, hereafter referred to as BNT) heterologous vaccination, although with some transient increased reactogenicity.

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  • Shaw RH
  • Stuart A
  • Greenland M
  • Liu X
  • Nguyen Van-Tam JS
  • Snape MD
Heterologous prime-boost COVID-19 vaccination: initial reactogenicity data.

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  • Borobia AM
  • Carcas AJ
  • Pérez-Olmeda M
  • et al.
Immunogenicity and reactogenicity of BNT162b2 booster in ChAdOx1-S-primed participants (CombiVacS): a multicentre, open-label, randomised, controlled, phase 2 trial.

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  • Kant R
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  • et al.
Serendipitous COVID-19 vaccine-mix in Uttar Pradesh, India: safety and immunogenicity assessment of a heterologous regime.

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  • Hillus D
  • Schwarz T
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  • et al.
Safety, reactogenicity, and immunogenicity of homologous and heterologous prime-boost immunisation with ChAdOx1 nCoV-19 and BNT162b2: a prospective cohort study.

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  • Powell AA
  • Power L
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  • et al.
Real-world data shows increased reactogenicity in adults after heterologous compared to homologous prime-boost COVID-19 vaccination, March-June 2021, England.

There is accruing evidence that the use of an mRNA boost after adenoviral-vector prime might enhance humoral and cellular responses against SARS-CoV-2, and that this response translates to efficacy against COVID-19.

8
  • Liu X
  • Shaw RH
  • Stuart ASV
  • et al.
Safety and immunogenicity of heterologous versus homologous prime-boost schedules with an adenoviral vectored and mRNA COVID-19 vaccine (Com-COV): a single-blind, randomised, non-inferiority trial.

14
  • Borobia AM
  • Carcas AJ
  • Pérez-Olmeda M
  • et al.
Immunogenicity and reactogenicity of BNT162b2 booster in ChAdOx1-S-primed participants (CombiVacS): a multicentre, open-label, randomised, controlled, phase 2 trial.

15
  • Kant R
  • Dwivedi G
  • Zaman K
  • et al.
Serendipitous COVID-19 vaccine-mix in Uttar Pradesh, India: safety and immunogenicity assessment of a heterologous regime.

16
  • Hillus D
  • Schwarz T
  • Tober-Lau P
  • et al.
Safety, reactogenicity, and immunogenicity of homologous and heterologous prime-boost immunisation with ChAdOx1 nCoV-19 and BNT162b2: a prospective cohort study.

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  • Barros-Martins J
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  • et al.
Immune responses against SARS-CoV-2 variants after heterologous and homologous ChAdOx1 nCoV-19/BNT162b2 vaccination.

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  • Benning L
  • Töllner M
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  • et al.
Heterologous ChAdOx1 nCoV-19/BNT162b2 prime-boost vaccination induces strong humoral responses among health care workers.

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  • Dimeglio C
  • Herin F
  • Da-Silva I
  • et al.
Heterologous ChAdOx1-S/BNT162b2 vaccination: neutralizing antibody response to SARS-CoV-2.

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  • Groß R
  • Zanoni M
  • Seidel A
  • et al.
Heterologous ChAdOx1 nCoV-19 and BNT162b2 prime-boost vaccination elicits potent neutralizing antibody responses and T cell reactivity.

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  • Schmidt T
  • Klemis V
  • Schub D
  • et al.
Immunogenicity and reactogenicity of heterologous ChAdOx1 nCoV-19/mRNA vaccination.

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  • Tenbusch M
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  • et al.
Heterologous prime-boost vaccination with ChAdOx1 nCoV-19 and BNT162b2.

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  • et al.
Immunogenicity and efficacy of heterologous ChadOx1/BNT162b2 vaccination.

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  • Gram MA
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  • et al.
Vaccine effectiveness when combining the ChAdOx1 vaccine as the first dose with an mRNA COVID-19 vaccine as the second dose.

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  • Nordström P
  • Ballin M
  • Nordström A
Effectiveness of heterologous ChAdOx1 nCoV-19 and mRNA prime-boost vaccination against symptomatic Covid-19 infection in Sweden: a nationwide cohort study.

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  • Vallée A
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  • et al.
An immunogenicity report for the comparison between heterologous and homologous prime-boost schedules with ChAdOx1-S and BNT162b2 vaccines.

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  • Normark J
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  • et al.
Heterologous ChAdOx1 nCoV-19 and mRNA-1273 vaccination.

29
  • Fabricius D
  • Ludwig C
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  • et al.
mRNA vaccines enhance neutralizing immunity against SARS-CoV-2 variants in convalescent and ChAdOx1-primed subjects.

The only other available data regarding heterologous schedules comes from preprints that suggest that adenoviral vaccines might be an effective boost for inactivated whole-virion prime.

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Heterologous prime-boost immunization with CoronaVac and Convidecia.

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  • Yorsaeng R
  • Vichaiwattana P
  • Klinfueng S
  • et al.
Immune response elicited from heterologous SARS-CoV-2 vaccination: Sinovac (CoronaVac) followed by AstraZeneca (Vaxzevria).

To date, there are no published data from randomised controlled trials examining the immunogenicity and safety of heterologous schedules of primary course COVID-19 vaccination with mixed mRNA, and none examining regimes containing a protein-subunit vaccine. NVX-CoV2373 (Novavax, hereafter referred to as NVX), a Matrix-M adjuvanted recombinant nanoparticle spike protein vaccine, has shown safety and efficacy in phase 3 trials and has been submitted to multiple regulatory agencies, including WHO, for licensing.
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Novavax
Novavax and Serum Institute of India announce submission to World Health Organization for emergency use listing of Novavax’ COVID-19 vaccine.

This vaccine can be transported and stored at standard refrigeration temperatures, making it particularly suitable for deployment in low-resource settings.

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  • Heath PT
  • Galiza EP
  • Baxter DN
  • et al.
Safety and efficacy of NVX-CoV2373 COVID-19 vaccine.

An mRNA vaccine mRNA-1273 (Moderna, hereafter referred to as m1273) has also shown high efficacy in clinical trials, with an acceptable safety profile, although with appreciable reactogenicity after second dose.

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  • Baden LR
  • El Sahly HM
  • Essink B
  • et al.
Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.

We have previously reported on the preliminary results of the Com-COV study, a randomised controlled trial of ChAd and BNT heterologous vaccination.
8
  • Liu X
  • Shaw RH
  • Stuart ASV
  • et al.
Safety and immunogenicity of heterologous versus homologous prime-boost schedules with an adenoviral vectored and mRNA COVID-19 vaccine (Com-COV): a single-blind, randomised, non-inferiority trial.

13
  • Shaw RH
  • Stuart A
  • Greenland M
  • Liu X
  • Nguyen Van-Tam JS
  • Snape MD
Heterologous prime-boost COVID-19 vaccination: initial reactogenicity data.

Here, we present findings from the related Com-COV2 study, a non-inferiority randomised controlled trial examining safety, reactogenicity, and immunogenicity of heterologous COVID-19 regimens including m1273 and NVX as boost vaccines for people who received a first dose of ChAd or BNT in the community COVID-19 vaccination programme in the UK, given after the prime at 8–12 weeks.

Methods

 Study design

Com-COV2 is a UK multicentre, single-blinded, randomised, phase 2, non-inferiority study, investigating the safety, reactogenicity, and immunogenicity of heterologous boost COVID-19 vaccine schedules. Recruitment occurred at nine National Health Service and academic institutions in England (appendix p 4). The trial was reviewed and approved by the South-Central Berkshire Research Ethics Committee (21/SC/0119), the University of Oxford, and the Medicines and Healthcare products Regulatory Agency.

Most participants were enrolled into the general cohort while a subset (n=150, selected on the basis of site capacity and participant availability) were enrolled into an immunology cohort that had mucosal and salivary samples collected, along with two additional blood tests to explore the kinetics of the immune responses.

We report the primary endpoint results, and reactogenicity profile from the day 28 visit. Safety data were collected up until Oct 5, 2021. The protocol is provided in the appendix (pp 45–123), and online.

 Participants

The study inclusion criteria were being aged 50 years or older and having received a single dose of either ChAd or BNT by routine immunisation 8–12 weeks earlier. Important exclusion criteria were history of confirmed SARS-CoV-2 infection, comorbidities that were considered severe or poorly controlled, anaphylaxis or allergy to a vaccine component, pregnancy, or intent to conceive, breastfeeding, and use of anticoagulants. Full details of the inclusion and exclusion criteria can be found in the protocol (appendix pp 69–71).

 Randomisation and masking

Computer generated randomisation lists were prepared by the study statistician. Participants were randomised (1:1:1) to receive a single dose of either the same vaccine as their prime dose (BNT or ChAd homologous schedule), m1273, or NVX (heterologous schedules).

Randomisation was done by random block sizes of three and six. Randomisation was stratified by study site, cohort (immunology or general), and prime vaccine (ChAd/BNT). Clinical research nurses who were not involved in endpoint evaluation did the randomisation using REDCap version 10.6.13 and prepared and administered the vaccine.

Participants were masked to boost vaccine allocation at enrolment. Blinding was maintained by completing pages and by preparing vaccines out of sight of participants, and use of the same syringe type across vaccines, with the drawn volume concealed by applying a masking tape. Following the introduction of COVID-19 vaccine certification in the UK, the study was amended on June 21, 2021, to allow individual participant unblinding where necessary to prevent disadvantage in accessing facilities or travel. This took place after all participants had completed the 28 day postvaccination diary monitoring period. Staff involved in study delivery, including in the assessment of adverse events, were aware of vaccine allocation. Laboratory staff processing the immunology samples remained blinded to vaccine allocation.

 Procedures

Participants meeting inclusion and exclusion criteria at the online screening (and additional subsequent telephone screening for some participants) were invited to attend a screening and enrolment visit (day 0). Participants who met final eligibility criteria and provided written informed consent were randomly assigned to a study group and vaccinated at the day 0 visit. Baseline haematological and biochemical blood tests were taken before vaccination at day 0.

Four vaccines were used in this study. ChAd was given as a 0·5 mL intramuscular injection into the upper arm. BNT was given as a 0·3 mL intramuscular injection into the upper arm. m1273 was given as a 0·5 mL intramuscular injection into the upper arm, and NVX as a 0·5 mL intramuscular dose injection into the upper arm.

Participants were observed for at least 15 min after vaccination. During the day 0 visit, participants were given an oral thermometer, tape measure, and diary card (electronic or paper) to record solicited, unsolicited, and medically attended adverse events with instructions. Study-site physicians reviewed the diary card regularly to identify, clinically action, and record adverse events, adverse events of special interest, and serious adverse events, with additional recording of events that were not entered into the diaries collected in person at study visits. The follow-up visit schedule can be found in the protocol (appendix pp 116–17).

Participants were instructed to notify trial teams if they received a positive SARS-CoV-2 test in the community. They were then invited for a study visit to allow for clinical assessment, collection of blood samples, and a nasopharyngeal swab, and were asked to complete a COVID-19 symptom diary for 7 days.

Sera were analysed at Nexelis (Laval, QC, Canada) to determine SARS-CoV-2 anti-spike IgG concentrations by ELISA (reported as ELISA laboratory units [ELU]/mL) and the 50% neutralising antibody titre (NT50) for SARS-CoV-2 pseudotype virus neutralisation assay, using a vesicular stomatitis virus backbone adapted to bear the 2019-nCOV SARS-CoV-2 spike protein.
35
  • Bewley KR
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  • Gagnon L
  • et al.
Quantification of SARS-CoV-2 neutralizing antibody by wild-type plaque reduction neutralization, microneutralization and pseudotyped virus neutralization assays.

The conversion factors to international standard units can be found in the appendix (pp 3–4). Sera from day 0 were analysed at Porton Down, Public Health England, by ECLIA (Cobas platform, Roche Diagnostics) to determine anti-SARS-CoV-2 nucleocapsid IgG status (reported as negative if below a cutoff index of 1·0). The samples from the immunology cohort (n=25) were also tested at Porton Down, UK Health Security Agency to measure the normalised 80% neutralising antibody titre (NT80) for live SARS-CoV-2 virus (lineage Victoria/01/2020) by microneutralisation assays.

35
  • Bewley KR
  • Coombes NS
  • Gagnon L
  • et al.
Quantification of SARS-CoV-2 neutralizing antibody by wild-type plaque reduction neutralization, microneutralization and pseudotyped virus neutralization assays.

For participants from five of nine selected sites, IFN-γ secreting T cells specific to whole spike protein epitopes, designed based on the Wuhan-Hu-1 sequence (YP_009724390.1), were detected using a modified T-SPOT-Discovery test done at Oxford Immunotec (Abingdon, UK) within 32 h of venepuncture, using the addition of T-Cell Xtend reagent to extend peripheral blood mononuclear cell (PBMC) survival. Participants at the other four sites did not have these taken as their sites were too far from the processing laboratory to enable sample integrity. T-cell frequencies were reported as spot forming cells (SFC) per 250 000 PBMCs with a lower limit of detection of one in 250 000 PBMCs. Intracellular cytokine staining was done on cryopreserved PBMCs, stimulated for 16 h with SARS-CoV-2 antigens (based on the Wuhan-Hu-1 sequence). Cells were stained with viability dye and fluorochrome-conjugated antibodies to CD3, CD4, and CD8 and further stained with fluorochrome-conjugated antibodies specific to IFN-γ, TNF-α, IL-2, IL-4, IL-5, and IL-13. Data are presented as percentage of CD4 or CD8 T cells expressing specific cytokines.

36
  • Peng Y
  • Mentzer AJ
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  • et al.
Broad and strong memory CD4+ and CD8+ T cells induced by SARS-CoV-2 in UK convalescent individuals following COVID-19.

Samples collected at day 28 after boost immunisation from a subgroup of seronegative participants (roughly 50 per arm) were selected pragmatically to test immunogenicity against Victoria/01/2020 (representative of wild-type), beta, and delta variants. Cryopreserved samples were tested against full spike protein from these variants using ELISpot at Oxford Immunotec. Microneutralisation assays to determine 50% focus reduction neutralisation titres (FRNT50) for live SARS-CoV-2 virus lineages (Victoria/01/2020, beta variant B.1.351, delta variant B.1.617.1) were done at the University of Oxford, Oxford, UK. The reduction in the number of infected foci is compared with a negative control well without an antibody.
37
  • Payne RP
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  • Austin JA
  • et al.
Immunogenicity of standard and extended dosing intervals of BNT162b2 mRNA vaccine.

 Outcomes

The primary outcome was non-inferiority of serum SARS-CoV-2 anti-spike IgG concentration 28 days after heterologous boost in comparison with homologous boost (the geometric mean ratio [GMR]) in participants who were seronegative for SARS CoV-2 nucleocapsid IgG at enrolment.

Secondary outcomes included safety and reactogenicity, measured through local and systemic solicited adverse events for 7 days after the boost, unsolicited adverse events for 28 days after the boost, medically attended adverse events up to 3 months after boost, and adverse events of special interest and serious adverse events throughout the study. Haematological and biochemical blood parameters were measured at day 0 and day 28 after the boost for all participants, and additionally at day 7 for those in the immunology cohort. Full definitions of safety outcomes can be found in the protocol (appendix pp 95–103). Immunological secondary outcomes include kinetics of SARS-CoV-2 anti-spike binding IgG concentration, live virus neutralisation titres, pseudotype virus neutralisation titres, cellular responses (measured by IFNγ ELISpot) in peripheral blood, and intracellular cytokines. The full list of outcome measures can be found in the protocol (appendix pp 66–67).

 Statistical analysis

The primary analysis of SARS-CoV-2 anti-spike IgG was carried out on a per-protocol basis. The per-protocol population consisted of participants who were seronegative for SARS-CoV-2 at baseline (defined by anti-nucleocapsid IgG negativity), had no confirmed SARS-CoV-2 infection within 14 days after boost vaccination, received the study vaccine as randomly assigned, had primary endpoint data available, and had no protocol deviations, whereas the modified intention-to-treat (mITT) population included the per-protocol population and participants with protocol deviations. The GMR was calculated as the antilogarithm of the difference between the mean of the log10 transformed titre in the heterologous arms and the corresponding homologous arm as the reference adjusting for study site and cohort (general or immunology) in the linear regression model. Results are presented separately for participants primed with ChAd and BNT in the community. We did four primary comparisons and therefore we presented one-sided 98·75% CIs to adjust for multiple testing for the primary outcome. Non-inferiority of a heterologous arm to its corresponding homologous arm was concluded if the lower 98·75% CI of a GMR lay above the non-inferiority margin of 0·63. This margin was chosen after discussion with policy makers and regulatory agencies to allow a sample size consistent with rapid study delivery, while still being close to the WHO criterion of 0·67 for licensing of new vaccines.
38
WHO
Guidelines on clinical evaluation of vaccines: regulatory expectations.

We also presented geometric means, adjusted GMRs, and corresponding two-sided 95% CIs in the mITT population. A heterologous arm was considered superior to its homologous arm if the lower limit of the two-sided 95% CI lies above one, and the homologous boost arm was superior if the upper limit of the two-sided 95% CI lies below one. The analyses for secondary immunological outcome were also carried out among the mITT population. For all immunological outcomes, censored data reported as below the lower limit of detection or lower limit of quantification were imputed with a value equal to half of the threshold before transformation. Correlations between different immunological outcomes were evaluated by Pearson correlation coefficients. Participants who received at least one dose of the study vaccines were included in the safety analysis. The proportion of participants with at least one safety event was reported by vaccine schedule.

The sample size calculation assumed a non-inferiority margin of a 0·63 fold difference between the geometric mean concentration (GMC) in the heterologous and homologous boost arms, a SD of 0·456 on log10 scale, and a true difference in GMC on log10 scale of zero. The study needed to recruit 175 participants in each arm to achieve 90% power at a one-sided 1·25% significance level, after adjusting for an attrition rate of 25% due to baseline SARS-CoV-2 seropositivity or loss to follow-up. Statistical analyses were done using R version 4.1.1 and SAS version 9.4.

 Role of the funding source

The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Results

From April 19 to May 14, 2021, 1174 participants across nine study sites in England were screened, with a total of 1072 enrolled and randomly assigned to a study group: 921 to the general cohort and 151 to the immunology cohort (figure 1).

Figure 1Trial profile

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BNT=BNT162b2 vaccine, Pfizer–BioNTech. ChAd=ChAdOx1 nCoV-19 vaccine, AstraZeneca. m1273=mRNA-1273 vaccine, Moderna. NVX=NVX-CoV2373 vaccine, Novavax.

Recruitment was stratified by community prime vaccines, with 540 participants having received ChAd and 532 BNT. Study site recruitment by community prime is presented in the appendix (p 4). All participants were immunised.
The median age of participants primed with ChAd was 63 years (range 50–75 years), 241 (45%) were female, and 50 (9%) were from minority ethnicities. In participants primed with BNT, the median age was 62 years (range 50–78 years), 210 (40%) were female, and 28 (5%) from minority ethnicities (table 1). There were higher rates of cardiovascular, respiratory, and diabetic comorbidity in the BNT primed groups; reflective of the earlier availability of BNT in the UK and vaccination prioritisation in the initial phases of the national vaccine roll-out. Median prime-boost interval was 9·4 (range 4·7–12·0) weeks for the ChAd community-prime group, and 9·6 (8·0–12·0) weeks for the BNT community-prime group (table 1).

Table 1Baseline characteristics by study arm

Data are n (%), mean (SD), or median (range). BNT=BNT162b2 vaccine, Pfizer–BioNTech. ChAd=ChAdOx1 nCoV-19 vaccine, AstraZeneca. m1273=mRNA-1273 vaccine, Moderna. NVX=NVXCoV2373 vaccine, Novavax.

Within each prime group, characteristics were well balanced between the three randomised arms, except for a male predominance in the BNT/NVX group (34% female; table 1). At baseline, 54 (5%) of 1072 participants were positive for anti-nucleocapsid IgG (cutoff index ≥1·0), with a range of 4–6% in the ChAd-primed groups and 3–7% in the BNT-primed groups (figure 1).
Participants who received a community prime with ChAd had a SARS-CoV-2 anti-spike IgG GMC at 28 days of 20 114 ELU/mL (95% CI 18 160 to 22 279) in the m1273 group, 5597 ELU/mL (4756 to 6586) in the NVX group, and 1971 ELU/mL (1718 to 2262) in the ChAd homologous group (per-protocol analysis; table 2). GMRs in the per-protocol population were 10·2 (one-sided 98·75% CI 8·4 to ∞) for ChAd/m1273 and 2·8 (2·2 to ∞) for ChAd/NVX when compared with ChAd/ChAd, with lower limits of both the CIs above the non-inferiority margin. Similar GMRs were observed in the mITT population, and the SARS-CoV-2 anti-spike IgG response to ChAd/m1273 and ChAd/NVX were both statistically superior to that of homologous ChAd/ChAd (table 2).

Table 2Summary of immunogenicity between heterologous and homologous prime-boost schedules at 28 days post boost

In the per-protocol analysis, data are n/N, GMC (95% CI), and GMR (98·75% CI); in the modified intention-to-treat analysis, data are n/N, GMC (95% CI), and GMR (95% CI). BNT=BNT162b2 vaccine, Pfizer–BioNTech. ChAd=ChAdOx1 nCoV-19 vaccine, AstraZeneca. ELU=ELISA laboratory units. FRNT50=50% focus reduction neutralising antibody titre. GMC=geometric mean concentration. GMR=geometric mean ratio. m1273=mRNA–1273 vaccine, Moderna. NT80=80% neutralising antibody titre. NVX=NVXCoV2373 vaccine, Novavax. NT50=50% neutralising antibody titre. SFC=spot-forming cells. PBMC=peripheral blood mononuclear cell.

In those who received BNT community prime, anti-spike IgG GMC was 22 978 ELU/mL (95% CI 20 597 to 25 636) in the m1273 group, 16 929 ELU/mL (15 025 to 19 075) in the BNT homologous group, and 8874 ELU/mL (7391 to 10 654) in the NVX group (per-protocol analysis, table 2). The BNT/m1273 group GMR was 1·3 (one-sided 98·75% CI 1·1 to ∞), with the lower limit of the CI above the non-inferiority margin, and was statistically superior to BNT/BNT. Although BNT/NVX did not meet the non-inferiority criterion at 0·5 (one-sided 98·75% CI 0·4 to ∞) there was an 18-fold rise (95% CI 15 to 21) from baseline (appendix pp 8–10). Similar results were reported for the mITT analysis (table 2).
In the mITT population, the GMRs between the live virus neutralising antibody titres (normalised FRNT50) against the Victoria strain, the live virus neutralising antibody titres (normalised NT80 by microneutralisation assays), and the pseudotype virus neutralising (NT50) antibody titres from the mITT analysis at 28 days after boost are broadly consistent with those of binding antibodies (table 2).
Cellular responses by T-cell ELISpot for ChAd community-primed participants were greatest in those boosted with NVX at 190 SFC per million PBMCs (95% CI 159–227), with a GMR of 4·8 (3·6–6·6) compared with participants receiving homologous ChAd (45 SFC per million PBMCs, 34–61). For those boosted with m1273 these respective values were 148 SFC per million PBMCs (118–187) and a GMR of 3·5 (2·5–4·8; table 2).
In BNT community-primed groups, cellular responses by T-cell ELISpot were higher in those receiving m1273 at 76 SFC per million PBMCs (95% CI 58–99) than in the homologous boost group at 49 SFC per million PBMCs (39–63); however, the GMC for NVX boost was below that of the homologous boost at 29 SFC per million PBMCs (22–38; table 2).
Correlations between cellular and humoral responses show a moderate correlation for the ChAd/ChAd group (correlation coefficient of 0·46), and weak correlation (Pearson correlation coefficients figure 2A). There is a strong correlation between live neutralising assays done at national reference and local laboratories (figure 2D).

Figure 2Correlation in the modified intention-to-treat population

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(A) SARS-CoV-2 anti-spike IgG and cellular response by IFN-γ ELISpot (the subset with cellular data only, n=582), (B) SARS-CoV-2 anti-spike IgG and live virus neutralising antibodies (the subset with live virus neutralising antibodies data only, n=289), (C) live virus neutralising antibodies and cellular response by IFN-γ ELISpot at 28 days after boost (the subset with live virus neutralising antibodies data only, n=289), (D) live virus neutralising antibodies tested at University of Oxford and those tested at Porton Down, UK Health Security Agency (the immunology cohort, n=123). Ellipses show the 95% CI for different vaccine schedules assuming multivariate normal distributions. Pearson correlation coefficients (95% CI) are presented for each vaccine schedule. BNT=BNT162b2 vaccine, Pfizer–BioNTech. ChAd=ChAdOx1 nCoV-19 vaccine, AstraZeneca. ELU=ELISA laboratory units. FRNT50=50% focus reduction neutralising antibody titre. m1273=mRNA-1273 vaccine, Moderna. NT80=80% neutralising antibody titre. NVX=NVXCoV2373 vaccine, Novavax. PBMCs=peripheral blood mononuclear cells. SFC=spot forming cells.

In the modified intention-to-treat population, the GMCs of anti-spike IgG at baseline were 381 (95% CI 347–418) and 526 (480–577) in the populations previously immunised with ChAd and BNT, respectively. While an increase in antibody concentrations at day 7 compared with baseline was observed in all groups, these tended to remain stable or decrease across all groups by day 28 except those receiving an NVX-CoV2373 boost, where there was a further increase from day 7 to day 28 (figure 3, appendix pp 6–9).

Figure 3Kinetics of immunogenicity by vaccine schedule

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Cellular response data were available in around 60% of sites, the other study sites did not collect plasma samples due to logistical challenges; data presented at day 7 and day 14 were from the immunology cohort only. Data presented from day 0 and day 28 are for all participants in the modified intention-to-treat-population. Boxplots represent the median and 25th and 75th percentiles; the whiskers extend up to the largest value, not greater than 1·5 times the IQR beyond the box. (A) Anti-spike IgG and (B) T-cell response. BNT=BNT162b2 vaccine, Pfizer–BioNTech. ChAd=ChAdOx1 nCoV-19 vaccine, AstraZeneca. ELU=ELISA laboratory units. m1273=mRNA−1273 vaccine, Moderna. NVX=NVXCoV2373 vaccine, Novavax. PBMCs=peripheral blood mononuclear cells. SFC=spot-forming cells.

With regard to cellular responses, participants who had received a community prime with ChAd had numerically higher baseline frequencies than did the BNT groups; responses peaked in all groups at day 14 but were maintained above baseline at day 28 (figure 3B). Responses of intracellular cytokines to SARS-COV-2 spike peptides by flow cytometry at day 0 and 14 after boost were similar across groups, with a predominantly T-helper-1 cell response (appendix pp 11–14).
In ChAd-primed groups, live virus neutralising antibody titres (FRNT50) were reduced according to point estimates across all groups for beta and delta variants, relative to Victoria, with the greatest decrement noted for beta (table 3, appendix pp 15–17). However, both heterologous groups maintained numerically higher titres than ChAd/ChAd, with the highest titres in ChAd/m1273 recipients, with GMRs of 15·8 (95% CI 9·6–26·1) against the beta variant and 17·4 (10·2–29·5) against the delta variant. Similarly, in BNT-primed groups, live virus neutralising antibody titres (FRNT50) across groups were numerically lower against beta and delta variants than to Victoria (table 3). There was no evidence of a difference in neutralising activity against Victoria, beta, and delta variants between the BNT-primed groups. Across all groups, little difference was noted in cellular responses to variants (table 3, appendix p 15).

Table 3Summary of immunogenicity against variants of concern between heterologous and homologous prime-boost schedules at 28 days after boost

Data shown are geometric mean (95% CI), unless otherwise specified. BNT=BNT162b2 vaccine, Pfizer–BioNTech. ChAd=ChAdOx1 nCoV-19 vaccine, AstraZeneca. ELU=ELISA laboratory units. FRNT50=50% focus reduction neutralising antibody titre. GMC=geometric mean concentration. GMR=geometric mean ratio. m1273=mRNA-1273 vaccine, Moderna. NVX=NVXCoV2373 vaccine, Novavax. PBMCs=peripheral blood mononuclear cells. SFC=spot-forming cells.

Local and systemic reactions were more frequent after m1273 boost vaccination compared with the homologous boost groups, with feverishness reported by 60 (33%) of 181 recipients of ChAd/m1273 compared with nine (5%) of 176 recipients of ChAd/ChAd (difference 28%, 95% CI 20–36), and by 39 (22%) of 176 recipients of BNT/m1273, compared with 16 (9%) of 175 recipients of BNT/BNT (13%, 5–21; figure 4). Similar increases were observed for chills, fatigue, fever, headache, joint pain, malaise, muscle ache, and nausea (figure 4). Most of the increase in reactogenicity was observed within the 48 h after immunisation (appendix pp 18–19).

Figure 4Severity of solicited local and systemic reactions in days 0–7 following boost vaccination by study arm as self-reported in participant electronic diaries

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Data are (A) local at vaccination site and (B) systemic. The severity presented is the participant’s highest severity across 7 days after vaccination for each solicited adverse event. Fever was defined as mild if 38·0°C to <38·5°C, moderate if 38·5°C to <39°C, and severe if ≥39·0°C. Feverish was self-reported feeling of feverishness. For systemic symptoms, grading was classified as mild if easily tolerated with no limitation on normal activity; moderate if some limitation of daily activity; severe if unable to perform normal daily activity. BNT=BNT162b2 vaccine, Pfizer–BioNTech. ChAd=ChAdOx1 nCoV-19 vaccine, AstraZeneca. m1273=mRNA-1273 vaccine, Moderna. NVX=NVXCoV2373 vaccine, Novavax.

By contrast, for NVX recipients, similar patterns were observed in systemic reactogenicity compared with the homologous study schedules. Local reactions were generally less frequent for NVX recipients, for example a difference in injection site pain of −49% (95% CI −50 to −30) for BNT/NVX compared with BNT/BNT. Paracetamol use mirrored the profile of systemic reactogenicity (appendix p 20).
Between enrolment and Oct 5, 2021, there were 589 adverse events in 357 participants (appendix p 21). Numbers of adverse events were similar across vaccine groups. Descriptions of all non-serious adverse events of grade 3 or worse are presented in the appendix (pp 22–25). There were five adverse events of special interest (excluding SARS-CoV-2 and COVID-19 events) and one deemed possibly related to study vaccination (eosinophilia, grade 2 severity; appendix p 26).
18 participants tested positive for SARS-CoV-2 or had a COVID-19 episode after enrolment (appendix pp 26–28). All cases occurred at least 2 months after a boost, coinciding with an epidemiological surge of infection nationally. A single participant was hospitalised but did not require invasive ventilation (appendix pp 28–30). There were 15 serious adverse events, none of which was considered related to study vaccination (appendix pp 28–30).
Biochemical and haematological blood results were taken at enrolment, day 7, and day 28 after boost and graded by modified US Food and Drug Administration toxicity scale (appendix pp 31–32, 120). There were no notable differences in biochemical adverse events between groups, with some minor variations reported in white blood cell indices. A single participant had grade 3 neutropenia at enrolment and day 7, which progressed to grade 4 at day 28 and was reported as an unrelated serious adverse event.

Discussion

Findings from this trial demonstrate that the immunogenicity of heterologous boost with m1273 following community prime with ChAd or BNT was non-inferior to the homologous-boost schedule. When heterologous boost was with NVX, only those primed with ChAd had titres of SARS-CoV-2 anti-spike IgG that were non-inferior to the homologous schedule, whereas BNT/NVX did not meet the non-inferiority threshold against homologous BNT. Nevertheless, within the limitations of comparing between non-randomised cohorts, SARS-CoV-2 anti-spike IgG titres induced by BNT/NVX were still above that of homologous ChAd, a schedule with demonstrated effectiveness of 65–70% against symptomatic SARS-CoV-2 infection and over 90% against hospitalisation and death.
39
UK Health Security Agency
COVID-19 vaccine surveillance report: 14 October 2021 (week 41).

Additionally, the T-cell response across all groups was greatest with ChAd/NVX, which might prove important in terms of durability of protection and protection against new SARS-CoV-2 variants.

40
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These data align with real-world evidence of robust effectiveness of mixed schedules against disease.

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Together, these findings support use of the mixed schedules studied here in rapid and flexible global deployment of COVID-19 vaccines. Accordingly, these schedules should be widely recognised for travel and certification.

Consistent with our previous results, schedules containing at least one mRNA dose showed the greatest binding and neutralising antibody responses, with the heterologous mRNA vaccination studied (BNT/m1273) generating a greater humoral immune response than the homologous BNT/BNT schedule. Given that m1273 contains an mRNA dose (100 μg) over three times that of BNT (30 μg), and that the m1273 containing schedules (BNT/m1273 and ChAd/m1273) generated the two highest antibody concentrations observed across Com-COV and this study, this might reflect a greater humoral immunogenicity of m1273 when compared with BNT, rather than a specific benefit of mixing mRNA vaccines.
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It is interesting to note that in the groups receiving an NVX boost, there is a modest increase in antibody titres after day 7; although the samples’ size are small, this finding warrants further investigation.

The strongest cellular immune response was seen with heterologous ChAd-primed schedules. ChAd/NVX showed the highest cellular response as measured by IFN-γ ELISPOT, and is similar to that seen with ChAd/BNT at a 28 day boost interval.
8
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Safety and immunogenicity of heterologous versus homologous prime-boost schedules with an adenoviral vectored and mRNA COVID-19 vaccine (Com-COV): a single-blind, randomised, non-inferiority trial.

The ChAd/m1273 schedule also produced a substantial cellular response, whereas both heterologous and homologous mRNA schedules (BNT/m1273 and BNT/BNT) showed lower responses. Strikingly, the BNT/NVX schedule produced a response below that of all other schedules studied, suggesting important differences in the ability of adenoviral-vectored and mRNA vaccines to prime T cells for subsequent stimulation by protein antigens.

These data do not show any convincing evidence of additional benefit of mixed schedules in maintaining neutralising activity against variants of concern, beyond that conferred by greater neutralising activity against the Victoria strain—ie, the decrease in neutralising activity elicited by mixed and homologous schedules was broadly similar. However, for the BNT/NVX recipients, it is notable that the apparent differences in neutralising activity against Victoria were less evident when testing against beta and delta strains. Whether this result is an artefact of a relatively small sample size, or suggestive of better preservation of neutralisation against variants of concern for this schedule, this finding warrants further research. Consistent with previous work, the T-cell response was maintained across all variants of concern, regardless of the schedule.
40
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This study supports our previous finding of mixed adenoviral-vectored and mRNA COVID-19 vaccine schedules being more reactogenic than homologous schedules, consistent with other studies examining BNT/ChAd.
13
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Additionally, there was evidence of increased reactogenicity for the heterologous over the homologous mRNA schedule (BNT/m1273 vs BNT/BNT). This effect could be due to the mixing of different mRNA vaccines, or m1273 being more reactogenic than BNT, potentially consistent with higher mRNA dosage; however, it is not possible to differentiate these possible causes in our study. By contrast, there was no evidence of increased reactogenicity for the NVX containing schedules. Importantly, within the limits of the sample size of this study, none of the schedules raised any safety concerns.

While most high-income countries have completed two-dose primary courses of COVID-19 vaccinations in adults, these data remain extremely relevant to the 94% of people in low-income countries who are yet to receive any doses.
1

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Of the mixed schedules studied, perhaps the most relevant to these countries is the ChAd/NVX, given that neither of these vaccines require ultra-low temperature storage and the low cost of ChAd. NVX has recently been the subject of a WHO Emergency Use Licence and should become available under the COVAX scheme.

42
Gavithe Vaccine Alliance
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Furthermore data for mixed schedules across platforms could help to inform the use of third-dose boosters, in addition with data from CoV-BOOST (ISRCTN12348322)

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and the recent work by Atmar and colleagues

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supporting use of mRNA vaccines for adenoviral-primed individuals. Such schedules could also allow avoidance of a second mRNA vaccine dose in adolescents, given concerns regarding myocarditis, and this hypothesis is being further studied in Com-COV3.

45
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ISRCTN12348322. Comparing COVID-19 vaccine schedule combinations in adolescents (Com-COV3).

46
Joint Committee on Vaccination and Immunisation
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This study has a number of limitations. The age range (50–78 years) and ethnicity (90·7% of participants primed with ChAd and 94·7% of those primed with BNT self-identified as White) of the study cohort limit generalisability of the reactogenicity and immunology results to younger populations and people who are not of White ethnicity. These groups might be more likely to receive heterologous COVID-19 vaccine schedules as a primary course, given age-associated safety concerns with the use of ChAd, and logistic constraints in lower-income regions.
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Any increased reactogenicity with heterologous regimes might be amplified in younger groups, as reported in studies of homologous vaccine schedules.

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The Lancet Infectious Diseases
COVID-19 vaccine equity and booster doses.

As participants were recruited after community prime, this dose was not randomised, meaning that some caution is required when comparing ChAd versus BNT community-primed groups, especially as there were higher rates of comorbidity in the BNT-primed groups. Additionally, the proportion of participants primed with ChAd versus BNT differed according to site, creating the potential for different amounts of exposure to SARS-CoV-2 between the groups. This fact is especially important when comparing the number of breakthrough infections observed between ChAd-primed and BNT-primed groups. Due to logistical and pragmatic constraints, we were not able to incorporate a full comparative schedule for all vaccines, and thus cannot provide evidence for the use of mixed mRNA schedules in both permutations, nor the effect of prime with a protein-based vaccine followed by ChAd or mRNA.

This research confirms previous evidence of mixed adenoviral and mRNA schedules as being safe, tolerable, and immunogenic alternatives to homologous schedules when given at an 8–12 weeks interval. It also provides new evidence on the response to mixed mRNA vaccinations in a randomised trial, and novel data for the incorporation of protein-based COVID-19 vaccines into heterologous schedules. These results provide reassurance that there are multiple appropriate options to complete primary immunisation in individuals primed with BNT or ChAd, which will facilitate rapid vaccine deployment globally.

MDS and JSN-V-T conceived the trial and MDS is the chief investigator. MDS, ASVS, RHS, and XL contributed to the protocol and design of the study. ASVS, ELP, RHS, and RW led the implementation of the study. XL and MG did the statistical analysis and have verified the underlying data. ASVS, RHS, MG, XL, and MDS drafted the report. All other authors contributed to the implementation and data collection. All authors reviewed and approved the final report. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Declaration of interests

MDS acts on behalf of the University of Oxford as an investigator on studies funded or sponsored by vaccine manufacturers, including AstraZeneca, GlaxoSmithKline, Pfizer, Novavax, Janssen, Medimmune, and MCM. He receives no personal financial payment for this work. JSN-V-T is seconded to the Department of Health and Social Care, England. AMC and DMF are investigators on studies funded by Pfizer and Unilever. They receive no personal financial payment for this work. AF is a member of the Joint Committee on Vaccination and Immunisation and chair of the WHO European Technical Advisory Group of Experts on Immunisation. He is an investigator or provides consultative advice on clinical trials and studies of COVID-19 vaccines produced by AstraZeneca, Janssen, Valneva, Pfizer, and Sanofi, and of other vaccines from these and other manufacturers, including GlaxoSmithKline, VPI Pharmaceuticals, Takeda, and Bionet Asia. He receives no personal remuneration or benefits for any of this work. SNF acts on behalf of University Hospital Southampton NHS Foundation Trust as an investigator or provides consultative advice on clinical trials and studies of COVID-19 and other vaccines funded or sponsored by vaccine manufacturers, including Janssen, Pfizer, AstraZeneca, GlaxoSmithKline, Novavax, Seqirus, Sanofi, Medimmune, Merck, and Valneva. He receives no personal financial payment for this work. PTH acts on behalf of St George’s University of London as an investigator on clinical trials of COVID-19 vaccines funded or sponsored by vaccine manufacturers, including Janssen, Pfizer, AstraZeneca, Novavax, and Valneva. He receives no personal financial payment for this work. CAG acts on behalf of University Hospitals Birmingham NHS Foundation Trust as an investigator on clinical trials and studies of COVID-19 and other vaccines funded or sponsored by vaccine manufacturers, including Janssen, Pfizer, AstraZeneca, Novavax, CureVac, Moderna, and Valneva. He receives no personal financial payment for this work. VL acts on behalf of University College London Hospitals NHS Foundation Trust as an investigator on clinical trials of COVID-19 vaccines funded or sponsored by vaccine manufacturers including Pfizer, AstraZeneca, and Valneva. He receives no personal financial payment for this work. TL is named as an inventor on a patent application covering the ChAd vaccine and is an occasional consultant to Vaccitech, unrelated to this work. ALG is named as an inventor on a patent covering use of a particular promoter construct that is often used in ChAdOx1-vectored vaccines and is incorporated in the ChAdOx1 nCoV-19 vaccine. ALG benefits from royalty income paid to the University of Oxford from sales of this vaccine by AstraZeneca and its sublicensees under the University’s revenue sharing policy. Oxford University has entered into a partnership with AstraZeneca for further development of ChAdOx1 nCoV-19. All other authors declare no competing interests.

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Will there ever be a cure for chronic nausea?

Feeling overwhelmed by the sensation that you’re going to be sick is one of the most miserably debilitating experiences — pity, then, people who live with nausea, feeling severely sick for days, weeks, even months on end.

Experts say that for many people living with long-term conditions, the nausea this causes can be the worst part of their illness.

‘It is so debilitating that it stops people living their daily lives,’ says Gareth Sanger, a professor of neuropharmacology at the Blizard Institute at Barts and The London School of Medicine and Dentistry. 

‘Research has found that patients are so desperate to escape chronic nausea that they say they would even be prepared to gamble on taking a theoretical pill that would have a 50/50 chance of curing them or killing them. It’s that bad.’

Experts say that for many people living with long-term conditions, the nausea this causes can be the worst part of their illness

Recent research found that a quarter of women affected by severe, persistent nausea and vomiting during pregnancy suffered suicidal thoughts as a result.

Chronic nausea is common, with as many as one in eight people suffering from it on a regular basis, and many more affected intermittently, according to experts including Dr Adam Farmer, a consultant gastroenterologist at the University Hospitals of North Midlands.

The causes range from chemotherapy to persistent stomach conditions (such as chronic indigestion). But it can also be a long-term effect of the winter vomiting virus and, more surprisingly, is linked to anxiety and depression — with at least one study suggesting that these conditions are such common triggers that patients should be checked for them before being sent for invasive tests for possible gastric causes.

Research published in General Hospital Psychiatry in 2002 found that patients with anxiety are three times more likely to suffer long-term nausea than people without the condition. 

One theory is that brain chemicals released as a result of anxiety disrupt the balance of bacteria in the gut, with the knock-on effect of causing nausea.

Yet precisely because chronic nausea can be linked to psychological factors, it is sometimes not rigorously investigated, says Peter Whorwell, a gastroenterologist at the Wythenshawe Hospital and professor of medicine at the University of Manchester. He adds: ‘It’s a very challenging symptom to diagnose and treat as there are so many different potential causes.’

Stark evidence of its harrowing effects emerged in a recent survey of women with hyperemesis gravidarum (HG), excessive nausea and vomiting in pregnancy. As well as revealing that a significant proportion of these women had suicidal thoughts, it found that 5 per cent said they’d terminated their pregnancies because of the condition, reported the journal Obstetric Medicine.

As many as 3.6 per cent of pregnancies are affected by HG — Kate Middleton, the Duchess of Cambridge, famously suffered it while carrying all three of her children.

The impact of such prolonged nausea can persist long after the sensations have abated. Nearly 30 per cent of women with HG suffered postnatal depression compared with 7 per cent of women who didn’t have HG, according to a study of more than 200 mothers published last year in the journal BMJ Open by researchers from Imperial College London.

Despite being so prevalent and disabling, there are no reliable treatments for HG-induced nausea. Professor Catherine Williamson from King’s College London, who led the latest HG study, says there is an ‘urgent need’ for further research into its causes.

‘By answering these questions, we will be able to develop more effective treatments,’ she says.

The problem is that scientists still know very little about what actually causes nausea, says Professor Sanger.

He told Good Health: ‘We can now stop vomiting with drugs but you can be left with horrible inescapable nausea symptoms. We thought that nausea would be easier to stop than vomiting. The reverse has proved true.’

While vomiting is a physical action involving muscle and gut convulsions, nausea is a sensation created by the nervous system and brain — and ‘science is still right down at the bottom rung of researching this’, he says.

‘What is known is that nausea sensations originate in the lower, most primitive part of our brains,’ he explains, referring to the brainstem at the bottom of the organ.

An area in the brainstem called the medulla oblongata receives sensory input from the rest of the body for causing feelings of nausea — these include motion that may cause travel sickness, and sickness from gut infections.

This area co-ordinates the physical act of vomiting as a primitive response to food poisoning, for instance. It also sends signals into areas of the higher part of the brain, including the insular cortex (associated with strong emotions such as fear), which generate the actual sensations of nausea.

One of the problems with ‘curing’ nausea is that the mechanism is protective — it evolved to stop us taking too much of something that could harm us.

Back in the 1980s, Professor Sanger led a team that created the first anti-sickness drugs for cancer patients who were undergoing chemotherapy.

The drugs stopped the patients vomiting by halting the action of a receptor called 5-HT3, which is normally involved in transferring information along the gut and controlling the wave-like actions of food and waste through it.

But the results were disappointing. ‘We thought that if we stopped the vomiting, then nausea would also be stopped,’ says Professor Sanger. ‘But the nausea was left behind unaffected.’ Some people are more prone to nausea than others. For example, women who vomit in the first trimester of pregnancy are more likely to vomit if they are given chemotherapy, while the under-50s are also more prone to experience nausea from chemotherapy — but the explanation for this is not clear.

Women are also more prone to cyclical vomiting syndrome — a rare condition which causes sufferers to be sick multiple times a day. ‘Without treatment they can die, as the repeated vomiting can deplete their levels of electrolytes [salts and minerals], and if potassium levels in particular drop too much your heart stops,’ says Professor Whorwell.

Professor Sanger is leading a team that is studying whether nerve-related disruptions in the way the stomach contracts to digest food may cause chronic nausea in some people with upper-gut disorders, such as gastroparesis, a rare condition where the stomach doesn’t empty properly.

‘The stomach is paralysed — it’s not emptying properly and this triggers nausea and sickness,’ says Professor Whorwell.

The winter vomiting bug — norovirus — can also cause this stomach-paralysing effect and long-term symptoms in some people, he says.

‘The first thing that happens is your stomach stops emptying so well — it’s the virus’s way of trying to stay in the body as long as possible — and some people develop persistent symptoms,’ says Professor Whorwell.

The difficulty in developing new treatments for nausea and vomiting is ‘compounded by the fact that the lab creatures most used for drug development — mice and rats — have evolved not to vomit,’ says Professor Sanger.

He says that the anti-psychotic drug olanzapine can provide some relief. ‘It affects about 12 brain receptors associated with nausea. However, it makes people feel sedated,’ he adds.

Less severe cases may respond to anti-vomiting drugs (called anti-emetics) which disrupt the signals travelling to or from the vomit centre in the brain, or slow the contractions in the gut.

For chronic nausea that anti-emetic drugs don’t touch, doctors can suggest only self-help measures such as eating little and often and avoiding fatty foods, because these delay the emptying of the stomach.

Otherwise, as Professor Sanger says: ‘We can only wait, continue researching, and hope.’

Additional reporting: Lucy Elkins

Omega watch 

Most of us know that omega-3 fatty acids are good for our health. But there are other important omegas, too. This week: Omega 9

Found in: Olive, nut and avocado oils are all great sources of omega 9.

What to know: Animal studies suggest omega 9s increase ‘good’ cholesterol and are beneficial for the brain. 

In a 2015 study on mice, these fatty acids were shown to have an anti-inflammatory effect and to improve cells’ sensitivity to insulin, helping remove sugar from the bloodstream.

 

 

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How Bat Moms Give Bat Pups Their Sense of Direction

It was more than a year into their project before they had enough data to realize their early results were no mistake. The signals of mother and baby bats had diverged because the mothers were carefully ditching their babies in trees while they searched for food.

“We couldn’t imagine that the mother would just leave a pup on a tree,” Dr. Goldshtein said.

Over five years of field work, they discerned a clear picture of what was going on. When Egyptian fruit bats pups are a few weeks old, mothers carry them from the cave at the start of the night, as usual, then fly to a tree and leave them — sort of like day care drop-off, without supervision. The mother returns throughout the night, perhaps to nurse and warm up the pup. When she’s done foraging, she carries the pup home.

The mother uses the same tree, or a few trees, over and over. As the pup gets older and heavier, the mother shifts to a drop-off tree closer to the cave.

Then, when the pup is around 10 weeks old, the mother leaves the cave, alone. The young bat emerges from the cave for its first solo trip — and, though there are thousands of trees nearby, flies straight to its most recent drop-off site. As it grows older, the pup uses the drop-off tree as a starting point for its own exploration.

“We were amazed to see these results,” Dr. Goldshtein said. Somehow, while hanging from their mothers’ bellies, baby bats learn their way around. The authors don’t know exactly how this learning happens. They think it may be by sight, although Egyptian fruit bats can echolocate using clicks of their tongue.

Mirjam Knörnschild, a behavioral ecologist at the Museum of Natural History in Berlin who studies bats, said that the authors had done a “great job” uncovering the poorly understood interactions between mother bats and pups. “The results strongly suggest that mothers actively help their pups with orientation,” she said.

Dr. Knörnschild was surprised that pups can memorize these routes while being carried upside-down and while never flying the routes themselves. “Personally,” she said, “I find it astonishing.”

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Viagra could be used to treat Alzheimer’s disease, study finds | Alzheimer’s

Viagra could be a useful treatment against Alzheimer’s disease, according to a US study.

Alzheimer’s disease, the most common form of age-related dementia, affects hundreds of millions of people worldwide. Despite mounting numbers of cases, however, there is currently no effective treatment.

Using a large gene-mapping network, researchers at the Cleveland Clinic integrated genetic and other data to determine which of more than 1,600 Food and Drug Administration-approved drugs could be an effective treatment for Alzheimer’s disease. They gave higher scores to drugs that target both amyloid and tau – two hallmarks of Alzheimer’s – compared with drugs that targeted just one or the other.

“Sildenafil, which has been shown to significantly improve cognition and memory in preclinical models, presented as the best drug candidate,” said Dr Feixiong Cheng, the study lead. Viagra is the brand name of sildenafil.

Researchers then used a database of claims from more than 7 million people in the US to examine the relationship between sildenafil and Alzheimer’s disease outcomes by comparing sildenafil users to non-users.

They found sildenafil users were 69% less likely to develop Alzheimer’s disease than non-sildenafil users after six years of follow-up. To further explore the drug’s potential effect on Alzheimer’s disease, researchers developed a lab model that showed that sildenafil increased brain cell growth and targeted tau proteins, offering insights into how it might influence disease-related brain changes. The findings were published in Nature Aging.

Cheng cautioned that the study does not demonstrate a causal relationship between sildenafil and Alzhemer’s disease. Randomised clinical trials involving both sexes with a placebo control were needed to determine sildenafil’s efficacy, he said.

Dr Ivan Koychev, a senior clinical researcher at the University of Oxford, who was not involved in the study, said it was “an exciting development” because “it points to a specific drug which may offer a new approach to treating the condition”.

Prof Tara Spires-Jones, deputy director of the Centre for Discovery Brain Sciences at the University of Edinburgh, said there were several important limitations to consider. “While these data are interesting scientifically, based on this study, I would not rush out to start taking sildenafil as a prevention for Alzheimer’s disease.”

Dr Susan Kohlhaas, director of research at Alzheimer’s Research UK, said: “Being able to repurpose a drug already licensed for other health conditions could help speed up the drug discovery process and bring about life-changing dementia treatments sooner.

“Importantly, this research doesn’t prove that sildenafil is responsible for reducing dementia risk, or that it slows or stops the disease. The only way to test this would be in a large-scale clinical trial measuring sildenafil effect against the usual standard of care.”

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Malaria kills 180,000 more people annually than previously thought, says WHO | Global development

The World Health Organization has called for a “massive, urgent” effort to get the new malaria vaccine into the arms of African children, as it warned that about 180,000 more people were dying annually from the disease than had previously been thought.

Dr Pedro Alonso, director of the WHO’s global malaria programme, said the RTS,S vaccine, recommended for widespread rollout in October, represented a historic opportunity to save tens of thousands of lives, mostly those of under-fives in sub-Saharan Africa.

But he warned that the global community risked “massive failure” if funding commitments aimed at boosting production and helping deployment of the vaccine were not rapidly made.

“What I think is the real barrier [is] international solidarity,” he said. “Is the world going to allow that there is a first malaria vaccine that can save the lives of tens of thousands of African children every year and they’re going to let it sit on a shelf? Or are they going to step up?”

The British pharmaceutical company GlaxoSmithKlein, which developed the RTS,S vaccine, has committed to donate up to 10m doses for use in the pilot programmes already under way, and to supply up to 15m doses annually.

However, with more than 240m cases globally last year, the potential demand could reach 80 to 100m doses annually, Alonso warned. “Therefore, this is a prime example of where international mechanisms will need to come into play,” he said.

“A vaccine that could save somewhere between 40 and 70-80,000 lives every year, of African children, is something that needs to be treated with the utmost ambition and sense of urgency. And therefore, a slow, gradual scale-up, if you ask me, would not be acceptable. This needs to be a massive, urgent operation to ensure that we can reach as many children as possible and as soon as possible.”

He added: “If the global health community does not respond to this challenge, it will represent a massive failure. I cannot imagine how different leaders, leaders of philanthropy or of financing institutions, are going to go to Africa and advocate for efforts to prevent childhood deaths if they don’t, first and foremost, support the deployment of this vaccine.”

Last week, the global vaccine alliance, Gavi, said its board had approved an initial $155.7m (£117m) for the rollout of RTS,S. The funding would help the introduction, procurement and delivery of the vaccine for eligible countries in sub-Saharan Africa from 2022 until 2025, it said.

Dr Abdourahmane Diallo, CEO of the RBM Partnership to End Malaria, said the announcement would give the private sector “a crucial motive to scale up” the rollout.

“We now call on leaders to step up investment to accelerate the development and delivery of more effective, transformative tools to combat the ever-evolving malaria parasite,” he said.

New figures released by the WHO on Monday underlined the scale of the problem, with a new, “more precise” method of counting estimating that 627,000 people died of malaria last year, 180,000 more than the total would have been according to the old methodology.

The vast majority of all malaria deaths – 96% – were in sub-Saharan Africa.

In its annual malaria report, the WHO said the “doomsday scenario” some had predicted at the beginning of the Covid-19 pandemic – that deaths from malaria would double as a result of disruption to treatment and services – had not materialised.

Nonetheless, it said, deaths had risen by nearly 70,000 last year, an increase of 12%, of which nearly 50,000 were attributable to disruptions during the pandemic. One main cause of disruption was that more than a quarter of insecticide-treated bed nets – the backbone of WHO efforts to combat malaria – were not distributed in 2020.

Faced with a slowing of progress in the fight against malaria, the WHO believes the vaccine could be a crucial new weapon, even though questions have been raised over its limited efficacy. Over four years of trials, RTS,S was found to prevent 39% of malaria cases and 29% of severe malaria cases.

But Alonso rejected concerns. “A reduction of 30% [in] severe cases of malaria means a massive public health impact, larger probably than any other vaccine against any other disease being used right now,” he said.

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The Pandemic Has Your Blood Pressure Rising? You’re Not Alone.

Last year was a tough one. Americans grappled with a global pandemic, the loss of loved ones, lockdowns that splintered social networks, stress, unemployment and depression.

It is probably no surprise that the nation’s blood pressure shot up.

On Monday, scientists reported that blood pressure measurements of nearly a half-million adults showed a significant rise last year, compared with the previous year.

These measurements describe the pressure of blood against the walls of the arteries. Over time, increased pressure can damage the heart, the brain, blood vessels, kidneys and eyes. Sexual function can also be affected.

“These are very important data that are not surprising, but are shocking,” said Dr. Donald M. Lloyd-Jones, president of the American Heart Association, who was not involved in the study.

“Even small changes in average blood pressure in the population,” he added, “can have a huge impact on the number of strokes, heart failure events and heart attacks that we’re likely to be seeing in the coming months.”

The study, published as a research letter in the journal Circulation, is a stark reminder that even in the midst of a pandemic that has claimed more than 785,000 American lives and disrupted access to health care, chronic health conditions must still be managed.

Almost half of all American adults have hypertension, or high blood pressure, a chronic condition referred to as a “silent killer” because it can have life-threatening consequences, though it produces few symptoms.

Hypertension may also put people at greater risk for severe disease if they are infected with the coronavirus. (The evidence for that link is mixed, according to the Centers for Disease Control and Prevention.)

The new study, by researchers at the Cleveland Clinic and Quest Diagnostics, examined data from hundreds of thousands of employees and family members in wellness programs that tracked blood pressure and other health indicators, like weight. The participants, from all 50 states and the District of Columbia, included people who had elevated blood pressure and normal blood pressure at the start of the study.

“We observed that people weren’t exercising as much during the pandemic, weren’t getting regular care, were drinking more and sleeping less,” said Dr. Luke Laffin, the lead author, a preventive cardiologist who is co-director of the Center for Blood Pressure Disorders at the Cleveland Clinic. “We wanted to know, was their blood pressure changing during the pandemic?”

The researchers found that blood pressure readings changed little from 2019 to the first three months of 2020, but increased significantly from April 2020 through December 2020, compared with the same period in 2019.

Blood pressure is measured in units of millimeters of mercury (mm Hg) and consists of two numbers. The first number refers to systolic pressure as the heart contracts, and the second number refers to diastolic pressure as the heart rests between beats. Normal blood pressure is said to be 120/80 mm Hg or less, although there is decades-long dispute about the optimal levels.

The new study found that the average monthly change from April 2020 to December 2020, compared with the previous year, was 1.10 mm Hg to 2.50 mm Hg for systolic blood pressure, and 0.14 to 0.53 for diastolic blood pressure.

The increases held true for both men and women, and in all age groups. Larger increases in both systolic and diastolic blood pressure were seen in women.

The average age of the study participants was just over 45, and slightly more than half were women. But critics said the failure to include information on the race and the ethnicity of participants was a significant weakness in the study, as hypertension is much more prevalent among Black Americans than among white or Hispanic Americans.

Black people have also been disproportionately affected by the pandemic. Dr. Laffin said information on race and ethnicity was available only for 6 percent of the study participants, so an analysis would not be meaningful.

But there is a big difference between Black Americans and white and Hispanic Americans when it comes to hypertension, said Dr. Kim Williams, a cardiologist at Rush University Medical Center in Chicago and an author of the national blood pressure guidelines that were issued in 2017.

“The hypertensive state has been epidemic in the African-American population for decades,” he said. “Our therapies have improved and our attempt at calling it out have improved, yet the gap is widening. And we know the pandemic has hit different cultures and different aspects of society in different ways.”

The causes of an overall increase in blood pressure are not clear, Dr. Laffin and his colleagues said. The reasons may include an increase in alcohol consumption, a decline in exercise, rising stress, a drop in doctors’ visits and less adherence to a medication regimen.

The researchers dismissed a possible effect of weight gain, known to raise blood pressure, saying that the men in the study had lost weight and that the women had not gained more weight than usual.

But other experts pointed out that average figures for weight gain might mask gains in segments of the population.

“It is probably multifactorial,” said Dr. Lloyd-Jones, referring to the overall rise in blood pressure. “But I think a critical piece is that we know so many people lost contact with the health care system, and lost control of blood pressure and diabetes.”

Americans must pay greater attention to overall health and the management of underlying medical conditions despite the pandemic, Dr. Laffin said, adding that the penalty for not doing so might outlast the coronavirus itself.

“There are also public health consequences from not seeing your doctor regularly, making poor dietary choices and not exercising,” he said. “If we think about the long-term implications, that’s potentially more profound.”

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Giant Study Finds Viagra Is Linked to Almost 70% Lower Risk of Alzheimer’s

Usage of the medication sildenafil – better known to most as the brand-name drug Viagra – is associated with dramatically reduced incidence of Alzheimer’s disease, new research suggests.

 

According to a study led by researchers at the Cleveland Clinic, taking sildenafil is tied to a nearly 70 percent lower risk of developing Alzheimer’s compared to non-users.

That’s based on an analysis of health insurance claim data from over 7.2 million people, in which records showed that claimants who took the medication were much less likely to develop Alzheimer’s over the next six years of follow up, compared to matched control patients who didn’t use sildenafil.

It’s important to note that observed associations like this – even on a huge scale – are not the same as proof of a causative effect. For example, it’s possible that the people in the cohort who took sildenafil might have something else to thank for their improved chances of not developing Alzheimer’s.

Nonetheless, the researchers say the correlation shown here – in addition to other indicators in the study – is enough to identify sildenafil as a promising candidate drug for Alzheimer’s disease, the viability of which can be explored in future randomized clinical trials designed to test whether causality does indeed exist.

 

“Notably, we found that sildenafil use reduced the likelihood of Alzheimer’s in individuals with coronary artery disease, hypertension, and type 2 diabetes, all of which are comorbidities significantly associated with risk of the disease, as well as in those without,” explains computational biologist and senior author of the study, Feixiong Cheng from the Cleveland Clinic.

It’s not the first time sildenafil use has been linked with better health outcomes, with the drug previously showing promise in a range of different scientific contexts, including cancer and malaria research among others.

Here, Cheng’s team began by building over a dozen endophenotype modules, using computational techniques to map genetic factors that could hypothetically govern the manifestation of Alzheimer’s disease.

With 13 of these modules in hand, the researchers then looked at what kinds of FDA-approved drugs might hypothetically help against the identified phenotypes.

Out of over 1,600 such medications already approved by the FDA, sildenafil turned out to be one of the most promising candidates.

That might sound baffling – given the drug is so far used in the main only for treating erectile dysfunction and pulmonary hypertension – in the research community, there were already signs the sildenafil compound might have other kinds of health benefits, given its interactions with the amyloid and tau proteins implicated in Alzheimer’s pathology.

 

“Recent studies show that the interplay between amyloid and tau is a greater contributor to Alzheimer’s than either by itself,” Cheng says.

“We hypothesized that drugs targeting the molecular network intersection of amyloid and tau endophenotypes should have the greatest potential for success… Sildenafil, which has been shown to significantly improve cognition and memory in preclinical models, presented as the best drug candidate.”

The hypothesis appears to be borne out by the health insurance data, with the team finding sildenafil users had a 69 percent reduced risk of Alzheimer’s disease compared to non-users – a reduction that was notably stronger than other kinds of medications also investigated in the study, including losartan, metformin, diltiazem, and glimepiride.

Of course, the researchers emphasize that none of this establishes causality, but on that front there may be other promising leads.

In separate experiments studying human brain cells in vitro to explore how sildenafil might confer protection against Alzheimer’s cognitive decline, the researchers observed that neurons treated with the drug showed elevated growth and reduced tau accumulation.

It’s early days, but those effects could well have something to do with the reduced chances of developing Alzheimer’s in the insurance cohort. To that end, it’s important to follow these leads further, the team says.

“We are now planning a mechanistic trial and a phase II randomized clinical trial to test causality and confirm sildenafil’s clinical benefits for Alzheimer’s patients,” Cheng says.

“We also foresee our approach being applied to other neurodegenerative diseases, including Parkinson’s disease and amyotrophic lateral sclerosis, to accelerate the drug discovery process.”

The findings are reported in Nature Aging.

 

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