Tag Archives: SARSCoV2

CRISPR Breakthrough Blocks SARS-CoV-2 Virus Replication in Early Lab Tests

Scientists have used CRISPR gene-editing technology to successfully block the transmission of the SARS-CoV-2 virus in infected human cells, according to research released Tuesday that could pave the way for COVID-19 treatments.

 

Writing in the journal Nature Communications, researchers in Australia said the tool was effective against viral transmissions in lab tests, adding that they hoped to begin animal trials soon.

CRISPR, which allows scientists to alter DNA sequences and modify gene function, has already shown promise in eliminating the genetic coding that drives the development of children’s cancer.

The team in Tuesday’s study used an enzyme, CRISPR-Cas13b, that binds to relevant RNA sequences on the novel coronavirus and degrades the genome it needs to replicate inside human cells.

Lead author Sharon Lewin from Australia’s Peter Doherty Institute for Infection and Immunity told AFP that the team had designed the CRISPR tool to recognize SARS-CoV-2, the virus responsible for COVID-19.

“Once the virus is recognized, the CRISPR enzyme is activated and chops up the virus,” she said.

“We targeted several parts of the virus – parts that are very stable and don’t change and parts that are highly changeable – and all worked very well in chopping up the virus.”

The technique also succeeded in stopping viral replication in samples of so-called “variants of concern” such as Alpha.

Although there are several COVID-19 vaccines already on the market, available treatment options are still relatively scarce and only partially effective.

 

‘Need better treatments’

Lewin said that using the CRISPR technique in widely available medicine was probably “years, not months” away.

But she insisted that the tool could still prove useful in tackling COVID-19.

“We still need better treatments for people who are hospitalized for COVID,” said Lewin.

“Our current choices here are limited and at best they reduce the risk of death by 30 percent.”

Lewin said the ideal treatment would be a simple antiviral, taken orally, that patients are given as soon as they test positive for COVID-19.

This would prevent them getting seriously ill, and in turn alleviate pressure on hospitals and care systems.

“This approach – test and treat – would only be feasible if we have a cheap, oral, and non-toxic antiviral. That’s what we hope to achieve one day with this gene scissors approach,” said Lewin.

Co-author Mohamed Fareh from the Peter MacCallum Cancer Centre said that another benefit of the research was its potential to be applied to other viral diseases.

“Unlike conventional anti-viral drugs, the power of this tool lies in its design-flexibility and adaptability, which make it a suitable drug against a multitude of pathogenic viruses including influenza, Ebola, and possibly HIV,” he said.

© Agence France-Presse

 

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Science, not speculation, is essential to determine how SARS-CoV-2 reached humans

On Feb 19, 2020, we, a group of physicians, veterinarians, epidemiologists, virologists, biologists, ecologists, and public health experts from around the world, joined together to express solidarity with our professional colleagues in China.
1
  • Calisher C
  • Carroll D
  • Colwell R
  • et al.
Statement in support of the scientists, public health professionals, and medical professionals of China combatting COVID-19.

Unsubstantiated allegations were being raised about the source of the COVID-19 outbreak and the integrity of our peers who were diligently working to learn more about the newly recognised virus, SARS-CoV-2, while struggling to care for the many patients admitted to hospital with severe illness in Wuhan and elsewhere in China.

It was the beginning of a global tragedy, the COVID-19 pandemic. According to WHO, as of July 2, 2021, the pandemic has resulted in 182 101 209 confirmed cases and 3 950 876 deaths, both undoubtedly underestimates of the real toll. The impact of the pandemic virtually everywhere in the world has been far worse than even these numbers suggest, with unprecedented additional social, cultural, political, and economic consequences that have exposed numerous flaws in our epidemic and pandemic preparedness and in local and global political and economic systems. We have observed escalations of conflicts that pit many parties against one another, including central government versus local government, young versus old, rich versus poor, people of colour versus white people, and health priorities versus the economy. The crisis has highlighted the urgent need to build a better understanding of how science proceeds and the complex, but critical, links science has with health, public health, and politics.

Recently, many of us have individually received inquiries asking whether we still support what we said in early 2020.
1
  • Calisher C
  • Carroll D
  • Colwell R
  • et al.
Statement in support of the scientists, public health professionals, and medical professionals of China combatting COVID-19.

The answer is clear: we reaffirm our expression of solidarity with those in China who confronted the outbreak then, and the many health professionals around the world who have since worked to exhaustion, and at personal risk, in the relentless and continuing battle against this virus. Our respect and gratitude have only grown with time.

The second intent of our original Correspondence was to express our working view that SARS-CoV-2 most likely originated in nature and not in a laboratory, on the basis of early genetic analysis of the new virus and well established evidence from previous emerging infectious diseases, including the coronaviruses that cause the common cold as well as the original SARS-CoV and MERS-CoV.
2
  • Forni D
  • Cagliani R
  • Clerici M
  • Sironi M
Molecular evolution of human coronavirus genomes.

Opinions, however, are neither data nor conclusions. Evidence obtained using the scientific method must inform our understanding and be the basis for interpretation of the available information. The process is not error-free, but it is self-correcting as good scientists endeavour to continually ask new questions, apply new methodologies as they are developed, and revise their conclusions through an open and transparent sharing of data and ongoing dialogue.

The critical question we must address now is, how did SARS-CoV-2 reach the human population? This is important because it is such insights that will drive what the world must urgently do to prevent another tragedy like COVID-19. We believe the strongest clue from new, credible, and peer-reviewed evidence in the scientific literature
3
  • Wacharapluesadee S
  • Tan CW
  • Maneeorn P
  • et al.
Evidence for SARS-CoV-2 related coronaviruses circulating in bats and pangolins in southeast Asia.

4
  • Zhou H
  • Ji J
  • Chen X
  • et al.
Identification of novel bat coronaviruses sheds light on the evolutionary origins of SARS-CoV-2 and related viruses.

5
Early appearance of two distinct genomic lineages of SARS-CoV-2 in different Wuhan wildlife markets suggests SARS-CoV-2 has a natural origin.

6
  • Latinne A
  • Hu B
  • Olival KJ
  • et al.
Origin and cross-species transmission of bat coronaviruses in China.

is that the virus evolved in nature, while suggestions of a laboratory-leak source of the pandemic remain without scientifically validated evidence that directly supports it in peer-reviewed scientific journals.

7
The COVID lab-leak hypothesis: what scientists do and don’t know.

8
The lab leak theory doesn’t hold up. The rush to find a conspiracy around the COVID-19 pandemic’s origins is driven by narrative, not evidence.

Careful and transparent collection of scientific information is essential to understand how the virus has spread and to develop strategies to mitigate the ongoing impact of COVID-19, whether it occurred wholly within nature or might somehow have reached the community via an alternative route, and prevent future pandemics. Allegations and conjecture are of no help, as they do not facilitate access to information and objective assessment of the pathway from a bat virus to a human pathogen that might help to prevent a future pandemic. Recrimination has not, and will not, encourage international cooperation and collaboration.
9
Nature
Protect scientific collaboration from geopolitics.

New viruses can emerge anywhere, so maintaining transparency and cooperation between scientists everywhere provides an essential early warning system. Cutting professional links and reducing data sharing will not make us safer.

We welcome calls for scientifically rigorous investigations.
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  • Bloom JD
  • Chan YA
  • Baric RS
  • et al.
Investigate the origins of COVID-19.

11
  • McNutt M
  • Anderson JL
  • Dzau VJ
Let scientific evidence determine origin of SARS-CoV-2, urge Presidents of the National Academies.

To accomplish this, we encourage WHO and scientific partners across the world to expeditiously move to continue and further extend their initial investigation with experts in China and the Chinese Government. WHO’s report from March, 2021,

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Joint WHO-China study
WHO-convened global study of origins of SARS-CoV-2: China part.

must be considered the beginning rather than the end of an inquiry, and we strongly support the G7 leaders’ call for “a timely, transparent, expert-led, and science-based WHO-convened phase 2 COVID-19 origins study”.

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G7 Cornwall UK 2021
Carbis Bay G7 Summit communiqué. Our shared agenda for global action to build back better.

We also understand that it might take years of field and laboratory study to assemble and link the data essential to reach rational and objective conclusions, but that is what the global scientific community must strive to do.

It is time to turn down the heat of the rhetoric and turn up the light of scientific inquiry if we are to be better prepared to stem the next pandemic, whenever it comes and wherever it begins. Meanwhile, people around the world continue to be infected by SARS-CoV-2, many are suffering severe disease and long-term sequelae, and too many are dying. Too many populations lack access to SARS-CoV-2 testing, COVID-19 treatments, and safe and effective vaccines, which will inevitably perpetuate the pandemic and its consequences. At the very least, we owe it to all who have suffered from COVID-19, as well as our families and the global community, to work collaboratively to end the pandemic and support international efforts to ensure vaccine equity, even as we prepare for the next pandemic.
14
  • Lurie N
  • Keusch GT
  • Dzau VJ
Urgent lessons from COVID 19: why the world needs a standing, coordinated system and sustainable financing for global research and development.

Having robust surveillance and detection systems in place across the globe is essential to detect and report new or evolving pathogens that can potentially unleash the next local or global threat, as required by the International Health Regulations. Equally essential will be ensuring that the field workforce, laboratory facilities, and the health-care community can all work under the safest conditions. Until this pandemic ends, we ask, as we did in February, 2020,
1
  • Calisher C
  • Carroll D
  • Colwell R
  • et al.
Statement in support of the scientists, public health professionals, and medical professionals of China combatting COVID-19.

for solidarity and rigorous scientific data.

PD’s remuneration is paid solely in the form of a salary from EcoHealth Alliance, a 501(c)(3) non-profit organisation. EcoHealth Alliance’s mission is to develop science-based solutions to prevent pandemics and promote conservation. Funding for this work comes from a range of US Government funding agencies and non-governmental sources. All past and current funders are listed publicly, and full financial accounts are filed annually and published. EcoHealth Alliance’s work in China was previously funded by the US National Institutes of Health (NIH) and the United States Agency for International Development (USAID). Neither PD nor EcoHealth Alliance have received funding from the People’s Republic of China. PD joined the WHO–China joint global study on the animal origins of SARS-CoV-2 towards the end of 2020 and is currently a member. As per WHO rules, this work is undertaken as an independent expert in a private capacity, not as an EcoHealth Alliance staff member. The work conducted by this study was published in March, 2021. EcoHealth Alliance’s work in China includes collaboration with a range of universities and governmental health and environmental science organisations, all of which are listed in prior publications, three of which received funding from US federal agencies as part of EcoHealth Alliance grants or cooperative agreements, as publicly reported by NIH. EcoHealth Alliance’s work in China is currently unfunded. All federally funded subcontractees are assessed and approved by the respective US federal agencies in advance and all funding sources are acknowledged in scientific publications as appropriate. EcoHealth Alliance’s work in China involves assessing the risk of viral spillover across the wildlife–livestock–human interface, and includes behavioural and serological surveys of people, and ecological and virological analyses of animals. This work includes the identification of viral sequences in bat samples, and has resulted in the isolation of three bat SARS-related coronaviruses that are now used as reagents to test therapeutics and vaccines. It also includes the production of a small number of recombinant bat coronaviruses to analyse cell entry and other characteristics of bat coronaviruses for which only the genetic sequences are available. NIH reviewed the planned recombinant virus work and deemed it does not meet the criteria that would warrant further specific review by its Potential Pandemic Pathogen Care and Oversight (P3CO) committee. All of EcoHealth Alliance’s work is reviewed and approved by appropriate research ethics committees, the Institutional Animal Care and Use Committee, institutional review boards for biomedical research involving human subjects, P3CO oversight administrators, and biosafety committees, as listed on all relevant publications. JMH is a member of the board of directors of EcoHealth Alliance. JL is a former Chief Veterinary Officer of the UN Food and Agriculture Organization. JSM is a member of the WHO International Health Regulations Emergency Committee for COVID-19, a member of the One Health High Level Expert Panel that advises the Food and Agriculture Organization of the UN, the World Organisation for Animal Health, the United Nations Environment Programme, and WHO, and a past member of the scientific advisory committee for the Center for Emerging Infectious Diseases of the Wuhan Institute of Virology (2008–11). JKM receives funding from USAID to the University of California at Davis, where she is a Principle Investigator, for the PREDICT Project, which funded viral detection and discovery capacity strengthening, One Health education, and global health capability strengthening around the world, including China and the Wuhan Institute of Virology. JKM is also a voluntary board member, with no compensation or financial interest, for the following not-for-profit collaborative consortia advocating for social and environmental equity, conservation, and global viral discovery in order to mitigate risks from viral spillover and pandemics: Global Virome Project, Gorilla Doctors, Bay Area Global Health Alliance, and UC Global Health Institute. JKM has reviewed for and consulted with numerous US state and federal agencies, including the NIH, Department of Defence, USAID, Food and Drug Administration, as well as non-governmental organisation such as the National Academies of Science, Engineering & Medicine and the American Association of Academic Medical Centers. JKM has ongoing collaborations with organisations, scientists, and other professionals in at least 40 countries, including China and the Wuhan Institute of Virology. JKM declares that her spouse owns and operates BHM Construction and A&J Investments, is an investor in VSP, and is a board member for San Francisco Achievers. SMP receives funding from an NIH grant for a project about SARS-CoV and host cell interactions and vaccine development. LE, HF, AEG, JKM, JSM, SMP, and LP have past or ongoing academic and scientific collaborations on coronavirus biology with colleagues in China and several other countries. LP directs a WHO COVID-19 Reference Laboratory. PD, HF, GTK, SKL, SMP, and LS are members of the Lancet Task Force on the Origins and Early Spread of COVID-19 & One Health Solutions to Future Pandemic Threats. JL is a member of the Lancet One Health Commission. All authors contributed to the 2020 Correspondence in The Lancet in support of the scientists, public health professionals, and medical professionals of China combatting COVID-19.

References

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    Statement in support of the scientists, public health professionals, and medical professionals of China combatting COVID-19.

    Lancet. 2020; 395: E42-E43

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    Molecular evolution of human coronavirus genomes.

    Trends Microbiol. 2017; 25: 35-48

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    Evidence for SARS-CoV-2 related coronaviruses circulating in bats and pangolins in southeast Asia.

    Nat Comms. 2021; 12: 972

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    Identification of novel bat coronaviruses sheds light on the evolutionary origins of SARS-CoV-2 and related viruses.

    Cell. 2021; ()

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    Early appearance of two distinct genomic lineages of SARS-CoV-2 in different Wuhan wildlife markets suggests SARS-CoV-2 has a natural origin.

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    • Latinne A
    • Hu B
    • Olival KJ
    • et al.

    Origin and cross-species transmission of bat coronaviruses in China.

    Nat Comms. 2020; 114235

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    The COVID lab-leak hypothesis: what scientists do and don’t know.

    Nature. 2021; 594: 313-315

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    The lab leak theory doesn’t hold up. The rush to find a conspiracy around the COVID-19 pandemic’s origins is driven by narrative, not evidence.

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    Protect scientific collaboration from geopolitics.

    Nature. 2021; 593: 477

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    • Bloom JD
    • Chan YA
    • Baric RS
    • et al.

    Investigate the origins of COVID-19.

    Science. 2021; 372: 694

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    • McNutt M
    • Anderson JL
    • Dzau VJ

    Let scientific evidence determine origin of SARS-CoV-2, urge Presidents of the National Academies.

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    WHO-convened global study of origins of SARS-CoV-2: China part.

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    Carbis Bay G7 Summit communiqué. Our shared agenda for global action to build back better.

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    • Keusch GT
    • Dzau VJ

    Urgent lessons from COVID 19: why the world needs a standing, coordinated system and sustainable financing for global research and development.

    Lancet. 2021; 397: 1229-1236

Linked Articles

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Susceptibility of Circulating SARS-CoV-2 Variants to Neutralization

To the Editor:

The emergence of two variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) — B.1.1.7 in the United Kingdom and B.1.351 in South Africa — has aroused concern that these variants may escape immunity resulting from either previous infection or vaccination. In an attempt to measure the resistance of these variants to neutralization elicited by infection or vaccination, we generated recombinant vesicular stomatitis virus–based SARS-CoV-2 pseudoviruses containing the spike protein of the Wuhan-1 reference strain (wild-type), the D614G mutation, and the B.1.1.7 and B.1.351 variants. (Details regarding the recombination process are provided in the Supplementary Appendix, available with the full text of this letter at NEJM.org.)

Neutralization of SARS-CoV-2 Pseudoviruses in Convalescent and Vaccinee Serum Samples.

Panel A shows the 50% pseudovirus neutralization titer (pVNT50) in convalescent serum collected from 34 recovered patients approximately 5 months after SARS-CoV-2 infection and in serum collected from 50 vaccinees who had received either the BBIBP-CorV or CoronaVac vaccine 2 to 3 weeks after the second dose against recombinant vesicular stomatitis virus–based SARS-CoV-2 pseudovirus bearing the Wuhan-1 (wild-type) spike protein. Box plots indicate the median and interquartile range (IQR); the whiskers represent 1.5 times the IQR. Panel B shows changes in the reciprocal serum pVNT50 titer in 34 convalescent serum samples against the D614G, B.1.1.7, and B.1.351 variants, as compared with wild-type virus. Panels C and D show changes in the reciprocal pVNT50 titer in serum samples obtained from the 25 recipients of the BBIBP-CorV vaccine and 25 recipients of the CoronaVac vaccine, respectively, against the D614G, B.1.1.7, and B.1.351 variants, as compared with wild-type virus. Factor changes in the geometric mean titer and 95% confidence interval (CI) in the pVNT50 titers, as compared with those for wild-type virus, are shown under the P values. Only P values of less than 0.05 (indicating significance) are shown. Each data point is the average of duplicate assay results. In each panel, the horizontal dashed line represents the lower limit of detection of the assay (titer, <30); this limit was assigned a value of 10 for geometric mean calculations and was considered to be seronegative. In all panels, calculations were performed with the use of the two-tailed Kruskal–Wallis test after adjustment for the false discovery rate.

We next evaluated pseudovirus resistance to neutralization using convalescent serum obtained from 34 patients 5 months after infection with coronavirus disease 2019 (Covid-19) and serum from 50 participants obtained 2 to 3 weeks after receipt of the second dose of inactivated-virus vaccines — BBIBP-CorV (Sinopharm)1 or CoronaVac (Sinovac)2 — which were developed in China (Table S1 in the Supplementary Appendix). We first determined the serum neutralizing-antibody titer against wild-type pseudovirus and observed similar geometric mean titers (GMTs) in serum obtained from convalescent patients and from vaccinees (Figure 1A), which suggested a low antibody response after two-dose inoculation induced by BBIBP-CorV or CoronaVac.1,2 Notably, undetectable neutralization titers were seen in 4 of 34 convalescent serum samples, in 6 of 25 BBIBP-CorV serum samples, and in 4 of 25 CoronaVac serum samples.

We next assessed the neutralizing activity of convalescent serum and vaccinee serum against D614G, B.1.1.7, and B.1.351 variants as compared with wild-type pseudovirus. The convalescent serum was significantly more effective (by a factor of 2.4; 95% confidence interval [CI], 1.9 to 3.0) in neutralizing the D614G pseudovirus, had a similar effect to that of the wild-type virus in neutralizing the B.1.1.7 variant, and was significantly less effective (by a factor of 0.5; 95% CI, 0.4 to 0.7) in neutralizing the B.1.351 pseudovirus (Figure 1B). Moreover, 9 of 30 convalescent serum samples showed complete loss of neutralizing activity against B.1.351. For the BBIBP-CorV vaccinee serum samples, although the GMTs of neutralization against the variants were not significantly different from the GMTs against the wild-type virus, 20 serum samples showed complete or partial loss of neutralization against B.1.351 (Figure 1C). For the CoronaVac vaccinee serum samples, we observed a marked decrease in the GMTs in the serum neutralization of B.1.1.7 (by a factor of 0.5; 95% CI, 0.3 to 0.7) and B.1.351 (by a factor of 0.3; 95% CI, 0.2 to 0.4). In addition, most of the serum samples showed complete or partial loss of neutralization against B.1.351 (Figure 1D).

Our findings suggest that B.1.1.7 showed little resistance to the neutralizing activity of convalescent or vaccinee serum, whereas B.1.351 showed more resistance to the neutralization of both convalescent serum (by a factor of 2) and vaccinee serum (by a factor of 2.5 to 3.3) than the wild-type virus. Most of the vaccinee serum samples that were tested lost neutralizing activity, a finding that was consistent with the results of other recent studies of neutralization by convalescent serum or serum obtained from recipients of messenger RNA or BBIBP-CorV vaccines.3-5 Our findings also highlight the importance of sustained viral monitoring and evaluation of the protective efficacy of vaccines in areas where variants are circulating.

Guo-Lin Wang, Ph.D.
Beijing Institute of Microbiology and Epidemiology, Beijing, China

Zhuang-Ye Wang, B.Med.
Dezhou Center for Disease Control and Prevention, Dezhou, China

Li-Jun Duan, B.Sc.
Beijing Institute of Microbiology and Epidemiology, Beijing, China

Qing-Chuan Meng, B.Med.
Ningjin County Community Health Service Center, Dezhou, China

Ming-Dong Jiang, M.Med.
Jing Cao, M.Med.
Dezhou Center for Disease Control and Prevention, Dezhou, China

Lin Yao, B.Med.
Ka-Li Zhu, B.Med.
Wu-Chun Cao, Ph.D.
Mai-Juan Ma, Ph.D.
Beijing Institute of Microbiology and Epidemiology, Beijing, China
[email protected], [email protected]

Supported by a grant (L202038) from the Beijing Natural Science Foundation and a grant (81773494) from the Natural Science Foundation of China, both to Dr. Ma.

Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.

This letter was published on April 6, 2021, at NEJM.org.

Dr. G.-L. Wang and Mr. Z.-Y. Wang contributed equally to this letter.

  1. 1. Xia S, Zhang Y, Wang Y, et al. Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBIBP-CorV: a randomised, double-blind, placebo-controlled, phase 1/2 trial. Lancet Infect Dis 2021;21:3951.

  2. 2. Zhang Y, Zeng G, Pan H, et al. Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18-59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. Lancet Infect Dis 2021;21:181192.

  3. 3. Huang B, Dai L, Wang H, et al. Neutralization of SARS-CoV-2 VOC 501Y.V2 by human antisera elicited by both inactivated BBIBP-CorV and recombinant dimeric RBD ZF2001 vaccines. February 2, 2021 (https://www.biorxiv.org/content/10.1101/2021.02.01.429069v1). preprint.

  4. 4. Liu Y, Liu J, Xia H, et al. Neutralizing activity of BNT162b2-elicited serum — preliminary report. N Engl J Med. DOI: 10.1056/NEJMc2102017.

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New SARS-CoV-2 Variants — Clinical, Public Health, and Vaccine Implications

To the Editor:

Across the world, there are multiple variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19). SARS-CoV-2 variants have been classified by the Centers for Disease Control and Prevention (CDC) as variants of interest, variants of concern, and variants of high consequence. Three new variants1 that have rapidly become dominant within their countries have aroused concerns: B.1.1.7 (also known as VOC-202012/01), 501Y.V2 (B.1.351), and P.1 (B.1.1.28.1).

The B.1.1.7 variant (23 mutations with 17 amino acid changes) was first described in the United Kingdom on December 14, 2020; the 501Y.V2 variant (23 mutations with 17 amino acid changes) was initially reported in South Africa on December 18, 2020; and the P.1 variant (approximately 35 mutations with 17 amino acid changes) was reported in Brazil on January 12, 2021. By February 22, 2021, the B.1.1.7 variant had been reported in 93 countries, the 501Y.V2 variant in 45, and the P.1 variant in 21.1 All three variants have the N501Y mutation, which changes the amino acid asparagine (N) to tyrosine (Y) at position 501 in the receptor-binding domain of the spike protein. The 501Y.V2 and P.1 variants both have two additional receptor-binding–domain mutations, K417N/T and E484K. These mutations increase the binding affinity of the receptor-binding domain to the angiotensin-converting enzyme 2 (ACE2) receptor. Four key concerns stemming from the emergence of the new variants are their effects on viral transmissibility, disease severity, reinfection rates (i.e., escape from natural immunity), and vaccine effectiveness (i.e., escape from vaccine-induced immunity).

The 501Y.V2 variant spread rapidly in South Africa, accounting for 11% of the viruses sequenced (44 of 392) in the first week of October 2020, for 60% of those sequenced (302 of 505) in the first week of November 2020, and for 87% of those sequenced (363 of 415) in the first week of December 2020. In Western Cape, a South African province where the 501Y.V2 variant is predominant, a threshold of 100,000 cases of Covid-19 was reached approximately 50% more quickly in the second wave of infection than in the first wave (54 vs. 107 days). The 501Y.V2 variant has been estimated to be 50%2 more transmissible than preexisting variants in South Africa, and B.1.1.7 to be between 43% and 82%3 more transmissible than preexisting variants in the United Kingdom.

Hospital admission rates of diagnosed cases and the clinical profile of admitted patients were similar in the first and second waves in Western Cape. However, a preliminary analysis by the National Institute of Communicable Diseases showed that the 501Y.V2 variant was associated with in-hospital mortality that was 20% higher in the second wave in South Africa than in the first wave. This finding was due mainly to the greater transmissibility of this variant, which rapidly overburdened health services and thus compromised timely access to hospital care and the quality of that care. Evidence from the United Kingdom indicates that the B.1.1.7 variant may be associated with a higher risk of death than preexisting variants in the United Kingdom.4 Although there is no evidence that antiviral agents and antiinflammatory treatments are any less effective with the emerging variants than with the preexisting variants, treatment with convalescent serum and monoclonal antibodies may not be as effective.

With regard to escape from natural immunity, the B.1.1.7 variant showed a modest decrease in neutralization activity, by a factor of 1.5, whereas the 501Y.V2 variant showed complete escape from neutralizing antibodies in 48% of convalescent serum samples (21 of 44) obtained from patients who had previously had Covid-19.5 A serendipitous finding from a vaccine trial in South Africa, in which 31% of the enrolled participants had previously been infected with SARS-CoV-2, was that the incidence of Covid-19, as confirmed on polymerase chain reaction, was 7.9% among seronegative enrollees and 4.4% among seropositive enrollees in the placebo group. This finding indicates that previous infection with preexisting variants may provide only partial protection from reinfection with the 501Y.V2 variant.

Summary Results on SARS-CoV-2 Vaccine Trial Efficacy and Viral Neutralization of the B.1.1.7, P.1, and 501Y.V2 Variants, as Compared with Preexisting Variants.

With regard to escape from vaccine-induced immunity, the B.1.1.7 variant showed modest decreases in neutralizing activity in serum samples obtained from vaccinated persons (Table 1). The serum neutralizing activity for the 501Y.V2 variant among vaccinated persons was lower by a factor of 1.6 to 8.6 for the BBIBP-CorV vaccine, the BNT162b2 vaccine, and the mRNA-1273 vaccine but was lower by a factor of up to 86, including complete immune escape, for the AZD1222 vaccine (Table 1). Neutralizing activity for the P.1 variant among vaccinated persons was lower by a factor of 6.7 for the BNT162b2 vaccine and by a factor of 4.5 for the mRNA-1273 vaccine (Table 1). The clinical relevance of the lower neutralization activity for either mild or severe Covid-19 is not clear, but efficacy in clinical trials was lower for all three vaccines tested in the midst of transmission of the 501Y.V2 variant in South Africa than efficacy in trials conducted in countries with preexisting variants. Efficacy was higher by a factor of 3.2 with the AZD1222 vaccine in the United Kingdom and Brazil than in South Africa (70% vs. 22%), higher by a factor of 1.8 with the NVX-CoV237 vaccine in the United Kingdom than in South Africa (89% vs. 49%), and higher by a factor of 1.3 with the Ad26.COV2.S vaccine in the United States than in South Africa (72% vs. 57%).

The emergence of these three new variants of concern highlight the importance of vigilance with genomic surveillance for the early identification of future variants. Recently, two more SARS-CoV-2 variants, B.1.427 and B.1.429, which were first detected in California, have been shown to be approximately 20% more transmissible than preexisting variants and have been classified by the CDC as variants of concern. The potential of variants to escape naturally induced and vaccine-induced immunity makes the development of next-generation vaccines that elicit broadly neutralizing activity against current and potential future variants a priority. The suppression of viral replication with both public health measures and the equitable distribution of vaccines is critical in reducing the risk of generation of new variants.

Salim S. Abdool Karim, M.B., Ch.B., Ph.D.
Centre for the AIDS Program of Research in South Africa, Durban, South Africa
[email protected]

Tulio de Oliveira, Ph.D.
KwaZulu-Natal Research Innovation and Sequencing Platform (KRISP), Durban, South Africa

Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.

This letter was published on March 24, 2021, at NEJM.org.

  1. 1. Pango lineages. Global report investigating novel coronavirus haplotypes. 2021 (https://cov-lineages.org/global_report.html).

  2. 2. Pearson CAB, Russell TW, Davies N, et al. Estimates of severity and transmissibility of novel SARS-CoV-2 variant 501Y.V2 in South Africa. London: CMMID Repository, 2021 (https://cmmid.github.io/topics/covid19/sa-novel-variant.html).

  3. 3. Davies N, Abbott S, Barnard RC, et al. Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England. London: CMMID Repository, 2020 (https://cmmid.github.io/topics/covid19/uk-novel-variant.html).

  4. 4. Horby P, Huntley C, Davies N, et al. NERVTAG paper on COVID-19 variant of concern B.1.1.7. London: Department of Health and Social Care, Scientific Advisory Group for Emergencies, January 2021 (https://www.gov.uk/government/publications/nervtag-paper-on-covid-19-variant-of-concern-b117).

  5. 5. Wibmer CK, Ayres F, Hermanus T, et al. SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma. January 19, 2021 (https://www.biorxiv.org/content/10.1101/2021.01.18.427166v1). preprint.

Summary Results on SARS-CoV-2 Vaccine Trial Efficacy and Viral Neutralization of the B.1.1.7, P.1, and 501Y.V2 Variants, as Compared with Preexisting Variants.*

Vaccine (Company) Preexisting Variants Neutralization by Pseudovirion or Live Viral Plaque Assay Efficacy in Settings with 501Y.V2 Variant
Sample Size Efficacy in Preventing Clinical Covid-19 Efficacy in Preventing Severe Covid-19 B.1.1.7 Variant P.1 Variant 501Y.V2 Variant
no. % (no. of events with vaccine vs. placebo) %
Ad26.COV2.S (Johnson & Johnson) 43,783 66 (NA) 85 (NA) NA NA NA 57†, 85‡
BNT162b2 (Pfizer) 34,922 95 (8 vs. 162) 90 (1 vs. 9) Decrease by 2× Decrease by 6.7× Decrease by ≤6.5× NA
mRNA-1273 (Moderna) 28,207 94 (11 vs. 185) 100 (0 vs. 30) Decrease by 1.8× Decrease by 4.5× Decrease by ≤8.6× NA
Sputnik V (Gamaleya) 19,866 92 (16 vs. 62) 100 (0 vs. 20) NA NA NA NA
AZD1222 (AstraZeneca) 17,177 67 (84 vs. 248) 100 (0 vs. 3) NA NA Decrease by ≤86×
to complete
immune escape
22§
NVX-CoV2373 (Novavax) 15,000 89 (6 vs. 56) 100 (0 vs. 1) Decrease by 1.8× NA NA 49§
CoronaVac (Sinovac)¶
Brazil 12,396 51 (NA) 100 (NA) NA NA NA NA
Turkey 7,371 91 (3 vs. 26) NA NA NA NA NA
BBIBP-CorV (Sinopharm) NA 79 (NA) NA NA NA Decrease by 1.6× NA

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SARS-CoV-2 transmission without symptoms | Science

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a potentially long incubation period and spreads opportunistically among those who are unaware they are infected. Asymptomatic COVID-19 cases are those that do not develop symptoms for the duration of infection, whereas presymptomatic cases develop symptoms later in the course of infection, but both are crucial drivers of transmission (1). Transmission without symptoms poses specific challenges for determining the infectious timeline and potential exposures. Early in the pandemic, most transmission was from undocumented cases, suggesting that spread was driven by people who were either asymptomatic or experiencing such mild disease that it was not recognized as COVID-19 (2). Contagious people without observable signs of illness make infection prevention efforts vulnerable to compliance with masking, distancing, hand hygiene, symptom screening, and ultimately, people staying home when possible. The lack of widespread testing in asymptomatic individuals further complicates COVID-19 mitigation and control efforts.

The true occurrence and transmission capacity of asymptomatic and presymptomatic infections are difficult to evaluate. Owing to insufficient surveillance testing (testing regardless of symptoms), presymptomatic cases lost to follow up, and unrecognized mild symptoms, symptomless cases are often undercounted or misclassified. It is virtually impossible to detect such cases without continuous community surveillance screening, which has not been widely implemented, or without effective contact tracing and testing. Beyond implementing general and often vague control measures, public health efforts have struggled to truly address symptomless transmission. Surveillance testing has predominantly been carried out in targeted populations such as long-term care facilities. Only certain industries, such as professional sports and entertainment, have implemented asymptomatic testing, but such data are not publicly available and these groups are not representative of the broader community. It is important to understand infectiousness and viral shedding, as well as the overall contribution of asymptomatic or presymptomatic cases to secondary cases.

The prevalence of symptomless cases is not precisely established. Early studies reported that asymptomatic cases accounted for 30 to 80% of infections (3), but more recent data point to a rate of asymptomatic cases between 17 and 30% (4). A recent systematic review of studies reporting SARS-CoV-2 diagnoses by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR, the standard molecular diagnostic test) and follow-up of symptoms found that the proportion of asymptomatic infections was 20% and that the rate of presymptomatic individuals could not be determined because of heterogeneity across studies (4). A limitation of such studies is measurement of asymptomatic status and selection bias. Often, large outbreaks driven by asymptomatic or presymptomatic transmission are restricted to specific populations or circumstances, such as in skilled nursing or long-term care facilities, where surveillance testing takes place (5). Because these are high-risk clinical environments, it is not surprising that symptomless transmission has been detected more frequently than in nonclinical settings, such as restaurants or offices, which lack access to testing or medically trained staff. The unknown prevalence of asymptomatic SARS-CoV-2 infections makes disease control and mitigation strategies inherently challenging.

Beyond assessing the prevalence of symptomless infections, it is vital to determine their risk for secondary transmission. Contact tracing is reliant on case identification, which generally involves testing of people with symptoms. This reliance on symptom-based testing, especially early in the pandemic, was also complicated by limited understanding of the full range of COVID-19 symptoms. The lack of surveillance testing makes analysis of secondary attack rates (the percentage of cases that result from one infected person within a defined group) for asymptomatic cases exceedingly difficult. In symptomatic COVID-19, infectiousness begins 2 days prior to symptom onset and for several days after, with reduced or undetectable viral shedding within the first week of symptom onset (5, 6). Viral shedding kinetics for asymptomatic COVID-19 is not well understood. Early in infection, individuals have similar viral loads regardless of eventual symptom severity, but asymptomatic cases have lower titers at peak replication, faster viral clearance, and thus a shorter infectious period (6).

Measuring the true impact of symptomless infections on transmission can be extremely confounding. Data on asymptomatic and presymptomatic cases who had close contacts but did not result in transmission are limited. Some studies found that asymptomatic cases were 42% less likely to transmit the virus, and observed lower secondary attack rates, whereas others have noted that regardless of a shorter infectious period, there is similar transmissibility for those with presymptomatic or asymptomatic COVID-19 in the first days of infection (6). Studies of presymptomatic transmission suggest that higher secondary attack rates are likely compared with asymptomatic cases (7). Moreover, analyses of contact tracing data indicated that at least 65% of transmission occurs prior to symptom onset (8). Another study found that only 12.6% of cases resulted from symptomless transmission (9). These discrepancies can be explained by several factors, including the misclassification of cases that were not followed up (4), but also that many are identified as a result of specific settings, such as superspreading events on cruise ships or in choir practice that result in rigorous investigations, and may not be representative of typical transmission events.

Determining the true transmission capability of asymptomatic and presymptomatic cases is inherently complex, but knowledge gaps should not detract from acknowledging their role in the spread of SARS-CoV-2. Those with symptoms appear to have higher secondary attack rates, but these cases are also more likely to present for testing and practice isolation because of obvious illness (10). The public health and infection prevention challenges rely on those without symptoms to self-quarantine and implement a suite of interventions, such as masking, social distancing, ventilation, and hand hygiene. However, emphasis on the degree of contagiousness rather than the knowledge that people without symptoms are generally contagious detracts from the public health threat that asymptomatic and presymptomatic infections pose and the need for continuous community-based surveillance and interventions.

The 2003 outbreak of the related SARS-CoV was eventually contained by using standard epidemiological approaches of isolating cases and tracing and quarantining contacts. This was effective because contagious patients could be easily identified through temperature and symptom screening. A major distinction from SARS-CoV is viral shedding of SARS-CoV-2 in the absence of observable clinical symptoms. Unlike SARS-CoV, SARS-CoV-2 viral loads are highest at symptom onset and up to a week after (6), which suggests substantial presymptomatic shedding. Therefore, people are likely contagious for a relatively long period and when they are unaware they have been infected or exposed. The minimum infectious dose required for transmission is also not known and likely varies depending on individual exposure and susceptibility. Although viral loads decline over the course of infection, the exact point at which someone stops being contagious is unclear, but probably occurs within 10 days of infection in most cases, provided symptoms are resolving.

Testing provides limited clarity on whether a person is likely to be contagious on the basis of estimated viral loads. Although people who have fully recovered from COVID-19 can continue to shed viral RNA and test positive by qRT-PCR in the absence of recoverable infectious SARS-CoV-2, as assessed by culture (1, 5, 6, 1114), these cases have not been associated with new clusters of transmission (12, 13). qRT-PCR detects viral RNA but not infectious virus particles. PCR cycle thresholds can be used to estimate viral load in nasal swabs, but do not always directly correlate with the quantity of infectious virus shed in respiratory particles. These particles are highly heterogeneous depending on various factors, including where in the respiratory tract cells are secreting infectious virus, breathing rate, and symptoms such as coughing (15). Not all exhaled particles contain infectious virus, and the amount of time that virus remains infectious after exhalation in respiratory particles can vary substantially depending on environmental conditions such as temperature and humidity, as well as the quantity of infectious particles being shed. Assays that measure infectious titer must be performed in biosafety level 3 (BSL-3) containment, so this cannot be routinely measured in clinical settings. Furthermore, qRT-PCR and rapid antigen tests can be performed in hours or minutes, compared to several days for determining infectious titer. Viral loads determined by qRT-PCR are, at best, a crude measure of actual infectious virus shedding, so further research is needed to establish viral loads in asymptomatic and presymptomatic cases (see the figure).

The biological basis for transmission without symptoms is poorly understood, even though it is common for respiratory viruses, including “common cold” pathogens such as rhinoviruses and other coronaviruses, to be spread by both contact and inhalation. Symptomless transmission is influenced by the timing and magnitude of the host response to infection, which is a major determinant of pathogenicity. Delayed or reduced host antiviral immune responses are closely linked to COVID-19 severity, suggesting a relationship between host response and symptom onset. This includes suppressed interferon-induced cytokine expression, which is linked to symptoms. As a gateway between the body and the environment, the upper respiratory tract is regularly exposed to external antigens. Thus, the nasal mucosa is a niche immune site in which antiviral responses are modulated by external factors (such as temperature or humidity) and host susceptibility (mucus, receptor distribution, and host response to infection) and may explain why symptomless spread is common for respiratory viruses.

Viral replication and symptom onset

The titer of infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the amount of viral RNA are generally lower in asymptomatic (A) than presymptomatic (Pre) COVID-19. There is likely to be a threshold at which a person becomes contagious, but this is not known. In presymptomatic patients, symptoms usually begin when viral load peaks, so there is a period of infectiousness when a person has no symptoms.

GRAPHIC: N. CARY/SCIENCE

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Viral replication and symptom onset

The titer of infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the amount of viral RNA are generally lower in asymptomatic (A) than presymptomatic (Pre) COVID-19. There is likely to be a threshold at which a person becomes contagious, but this is not known. In presymptomatic patients, symptoms usually begin when viral load peaks, so there is a period of infectiousness when a person has no symptoms.

GRAPHIC: N. CARY/SCIENCE

With many contagious people experiencing no symptoms and in the absence of robust surveillance testing for asymptomatic or presymptomatic infections, it is critical to maximize efforts to reduce transmission risk in the community. Academic debates about the frequency of different transmission routes reframe exposure risk reduction as a dichotomy rather than a spectrum, confusing rather than informing guidance. Rather than targeting transmission by either inhalation or contact, infection prevention efforts should focus instead on the additive nature of risk reduction and the need for continued vigilance in community-based infection prevention measures, including masks, distancing, avoiding enclosed spaces, ventilation, hand hygiene, and disinfection.

Transmission without symptoms critically contributes to the unabated spread of SARS-CoV-2 and presents a considerable infection prevention challenge. Although asymptomatic individuals appear to be contagious for a shorter period of time and may pose a lower transmission risk, they still pose a substantial public health risk as they are more likely to be out in the community. It is unclear how vaccination will affect the number of asymptomatic cases, although preliminary data suggest that mass immunization will reduce infection overall, thus reducing transmission. For presymptomatic cases, research has shown that viral shedding is highest just before and for a few days after symptoms begin, which is a critical time to ensure that individuals who may not realize they have been exposed stay home when possible and practice risk reduction efforts when in the community. Until there is widespread implementation of robust surveillance and epidemiological measures that allow us to put out these smokeless fires, the COVID-19 pandemic cannot be fully extinguished.

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