Summary
Background
Current UK vaccination policy is to offer future COVID-19 booster doses to individuals at high risk of serious illness from COVID-19, but it is still uncertain which groups of the population could benefit most. In response to an urgent request from the UK Joint Committee on Vaccination and Immunisation, we aimed to identify risk factors for severe COVID-19 outcomes (ie, COVID-19-related hospitalisation or death) in individuals who had completed their primary COVID-19 vaccination schedule and had received the first booster vaccine.
Methods
We constructed prospective cohorts across all four UK nations through linkages of primary care, RT-PCR testing, vaccination, hospitalisation, and mortality data on 30 million people. We included individuals who received primary vaccine doses of BNT162b2 (tozinameran; Pfizer–BioNTech) or ChAdOx1 nCoV-19 (Oxford–AstraZeneca) vaccines in our initial analyses. We then restricted analyses to those given a BNT162b2 or mRNA-1273 (elasomeran; Moderna) booster and had a severe COVID-19 outcome between Dec 20, 2021, and Feb 28, 2022 (when the omicron (B.1.1.529) variant was dominant). We fitted time-dependent Poisson regression models and calculated adjusted rate ratios (aRRs) and 95% CIs for the associations between risk factors and COVID-19-related hospitalisation or death. We adjusted for a range of potential covariates, including age, sex, comorbidities, and previous SARS-CoV-2 infection. Stratified analyses were conducted by vaccine type. We then did pooled analyses across UK nations using fixed-effect meta-analyses.
Findings
Between Dec 8, 2020, and Feb 28, 2022, 16 208 600 individuals completed their primary vaccine schedule and 13 836 390 individuals received a booster dose. Between Dec 20, 2021, and Feb 28, 2022, 59 510 (0·4%) of the primary vaccine group and 26 100 (0·2%) of those who received their booster had severe COVID-19 outcomes. The risk of severe COVID-19 outcomes reduced after receiving the booster (rate change: 8·8 events per 1000 person-years to 7·6 events per 1000 person-years). Older adults (≥80 years vs 18–49 years; aRR 3·60 [95% CI 3·45–3·75]), those with comorbidities (≥5 comorbidities vs none; 9·51 [9·07–9·97]), being male (male vs female; 1·23 [1·20–1·26]), and those with certain underlying health conditions—in particular, individuals receiving immunosuppressants (yes vs no; 5·80 [5·53–6·09])—and those with chronic kidney disease (stage 5 vs no; 3·71 [2·90–4·74]) remained at high risk despite the initial booster. Individuals with a history of COVID-19 infection were at reduced risk (infected ≥9 months before booster dose vs no previous infection; aRR 0·41 [95% CI 0·29–0·58]).
Interpretation
Older people, those with multimorbidity, and those with specific underlying health conditions remain at increased risk of COVID-19 hospitalisation and death after the initial vaccine booster and should, therefore, be prioritised for additional boosters, including novel optimised versions, and the increasing array of COVID-19 therapeutics.
Funding
National Core Studies–Immunity, UK Research and Innovation (Medical Research Council), Health Data Research UK, the Scottish Government, and the University of Edinburgh.
Introduction
Coronavirus (COVID-19) vaccinations.
Three vaccines have mainly been used in the UK—namely, BNT162b2 (tozinameran; Pfizer–BioNTech), ChAdOx1 nCoV-19 (Oxford–AstraZeneca), and mRNA-1273 (elasomeran; Moderna).
COVID-19: the green book, chapter 14a.
In the UK, the primary vaccination schedule is two doses for the majority of the population or three doses for people who are immunosuppressed. Booster doses have been offered in the UK since September, 2021, initially for groups at high risk of serious illness from COVID-19. However, the rapid emergence of the more transmissible omicron (B.1.1.529) variant of concern (relative to delta [B.1.617.2])—which was first seen in the UK in late November, 2021, and became the dominant variant by mid-December—led to considerable concern in public, professional, and government circles, resulting in a policy initiative to fast-track the roll-out of the booster vaccine, including to younger people (all those aged 40 years and older), in an attempt to prevent yet another UK-wide lockdown over Christmas, 2021. From Nov 29, 2021, booster doses were then extended to those aged 18 years and over, with a recommended gap of 3 months after primary vaccination.
,
- Sheikh A
- Kerr S
- Woolhouse M
- et al.
,
How to get a booster dose of the coronavirus (COVID-19) vaccine.
Evidence before this study
We searched PubMed, medRxiv, and SSRN on June 27, 2022, for English studies investigating severe COVID-19 outcomes after vaccination using the search terms “COVID-19 breakthrough infections (MeSH)”, “COVID-19 vaccines (MeSH)”, and “COVID-19 (MeSH)”. Our searches identified 133 studies. Previous evidence has consistently shown that vaccination with the first booster dose reduces the risk of SARS-CoV-2 infection, and COVID-19-related hospitalisation and death. An analysis of national data from Israel estimated first booster dose of BNT162b2 mRNA vaccine effectiveness of 92% (95% CI 82–97) against severe COVID-19. Another national study from Qatar in the omicron era estimated vaccine effectiveness of BNT162b2 against severe COVID-19 as 77% (95% CI 56–88). We have previously reported on risk factors for severe COVID-19 outcomes after first and second vaccine doses of the primary schedule, but there is little population-based evidence about the factors associated with COVID-19-related hospitalisation and death after the first booster dose in the omicron era.
Added value of this study
We found an increased risk of severe COVID-19 outcomes beginning 10 weeks after completing the primary vaccination schedule, with this risk reducing after the first booster dose. This UK-wide analysis, in addition to confirming some of the previously identified risk factors for severe COVID-19 outcomes such as older age and use of immunosuppressants, has also highlighted additional risk factors, such as chronic kidney disease, neurological disorders, heart failure, and chronic obstructive pulmonary disease. Most importantly, we demonstrate a substantive increased risk associated with high multimorbidity.
Implications of all the available evidence
As the pandemic continues to evolve, vaccination programmes and mitigation strategies need to evolve to prioritise those at highest risk of severe COVID-19 outcomes. This UK-wide population-based investigation has found that, after the first vaccine booster, older people, those with high multimorbidity, and those with certain underlying health conditions remain at highest risk of COVID-19-related hospitalisation and death. The UK’s Joint Commission on Vaccination and Immunisation should consider prioritising these individuals for the forthcoming autumn booster dose programme, ideally with novel optimised vaccines, and COVID-19 therapeutics.
- Kuhlmann C
- Mayer CK
- Claassen M
- et al.
Work in Israel showed that, although a booster reduced the risk of severe COVID-19 outcomes (ie, COVID-19-related hospitalisation or death), these events continued at a rate of 1·68 events per 1000 person-years.
- Bar-On YM
- Goldberg Y
- Mandel M
- et al.
In another study done in Israel,
- Barda N
- Dagan N
- Cohen C
- et al.
vaccine effectiveness of the first booster dose against severe COVID-19 illness was estimated to be 92%. In a study by Arbel and colleagues,
- Arbel R
- Hammerman A
- Sergienko R
- et al.
compared with individuals who were not boosted, COVID-19 mortality was reduced by 90% in individuals who received a booster dose. Although these studies suggest that the first booster dose has been beneficial, there is little evidence about factors associated with severe COVID-19 outcomes in the boosted population.
- Agrawal U
- Katikireddi SV
- McCowan C
- et al.
reported that older age, multimorbidity, hospitalisation in the 4 weeks before vaccination, working in a high-risk occupation, being a care home resident, socioeconomic deprivation, being male, and being an ex-smoker increased the risk of severe COVID-19 outcomes after the first dose of the primary vaccination schedule. However, this analysis was done when the alpha (B.1.1.7) variant was dominant. It is crucial to characterise factors associated with increased risk for individuals after the first booster dose so that they can be prioritised for future boosters and potentially also be offered COVID-19 therapeutics.
Interim statement on the use of additional booster doses of Emergency Use Listed mRNA vaccines against COVID-19.
Current UK vaccination policy is to offer future booster doses to individuals at high risk, but it is still uncertain which groups of the population could benefit most.
Vulnerable adults set for autumn COVID booster jab.
In response to an urgent request from the UK’s Joint Commission on Vaccination and Immunisation (JCVI), we sought to describe the clinical and demographic characteristics of individuals associated with increased risk of COVID-19-related hospitalisation and mortality at 14 days or more after receiving the booster dose of the BNT162b2 or mRNA-1273 vaccine. Working with population-based data from across the UK’s four nations offered us the opportunity to populate data gaps in individual country datasets (eg, for HIV) and generate precise estimates for rare risk groups.
Results
Table 1Combined sample characteristics and rates of severe COVID-19 outcomes for individuals who received primary vaccine doses across England (N=11·4 million), Northern Ireland (N=40 000), Scotland (N=3·1 million), and Wales (N=1·6 million)
Rates are per 1000 person-years.
Table 2Combined sample characteristics and rates of severe COVID-19 outcomes for individuals who received a booster dose, across England (N=9·7 million), Northern Ireland (N=24 000), Scotland (N=2·7 million), and Wales (N=1·4 million)
Rates are per 1000 person-years.
Risk factors associated with severe COVID-19 outcomes after receiving a booster dose were similar to those associated with worse outcomes after completion of the primary vaccination schedule. There was an increased risk of severe COVID-19 outcomes 9 weeks or more after receiving a booster dose of BNT162b2 or mRNA-1273 vaccine (≥9 weeks vs 3–5 weeks; aRR 1·20 [95% CI 1·07–1·35]). Individuals with a greater number of comorbidities (≥5 comorbidities vs none; 9·51 [9·07–9·97]), who were older (aged ≥80 years vs 18–49 years; 3·60 [3·45–3·75]), or who were male (male vs female; 1·23 [1·20–1·26]) were also associated with increased risk of severe COVID-19 outcomes.
Table 3Pooled analyses of Poisson-adjusted rate ratios for demographic and clinical characteristics associated with COVID-19-related hospitalisation or death among individuals who received booster doses
Overall estimates are shown as well as those stratified by type of vaccine at second dose.
Discussion
This UK-wide analysis has identified those who remain at risk of severe COVID-19 outcomes after the first vaccine booster dose. Our findings identified risk factors that have been previously reported (eg, age and being immunosuppressed), but we also identified a range of additional risk groups and highlighted the substantial increased risk posed by multimorbidity. These risk factors translated into both analyses in a dose-dependent manner. Our results showed that there were benefits of the first vaccine booster dose, indicated by the reduced rate of severe COVID-19 outcomes after booster doses, changing from 8·8 events per 1000 person-years (59 510 total events) to 7·6 events per 1000 person-years (26 100 total events). Although lower, this risk is still appreciable in public health terms, necessitating consideration of further booster doses, beginning with those at highest risk. These insights now need to be factored into plans for the roll-out of the autumn COVID-19 booster programme and those who should be prioritised for COVID-19 therapeutics.
- Mulholland RH
- Vasileiou E
- Simpson CR
- et al.
,
- Vasileiou E
- Simpson CR
- Shi T
- et al.
Our decision to analyse population-based cohorts across different UK nations offered the opportunity to fill data gaps present in individual nations (eg, HIV exceptionalism in the devolved administrations). Additional strengths included our ability to adjust for a range of covariates, and the pooling of data from across the UK, thereby allowing for precision of estimates for groups of patients with rare conditions. Confining our analysis to the period during which omicron was dominant was an additional strength.
- Sheikh A
- Kerr S
- Woolhouse M
- et al.
Moreover, a few of the earlier hospital admissions in the study might have not been caused by omicron, considering that no variant has ever been 100% dominant.
- Piernas C
- Patone M
- Astbury NM
- et al.
Our findings also suggest that all groups aged 65 years and over were at increased risk of serious outcomes relative to the reference group (aged 18–49 years), indicating the need to consider the second dose of booster in these older adults. Our analysis is in agreement with findings from other work,
- Bar-On YM
- Goldberg Y
- Mandel M
- et al.
,
- Barda N
- Dagan N
- Cohen C
- et al.
,
- Arbel R
- Hammerman A
- Sergienko R
- et al.
which has shown reduction in severe COVID-19 outcomes after booster. Our findings suggest that there were around 8 severe COVID-19 events per 1000 person-years, which is higher than the figure reported in a study in Israel.
- Bar-On YM
- Goldberg Y
- Mandel M
- et al.
However, the timeframe of this study and that of Bar-On and colleagues
- Bar-On YM
- Goldberg Y
- Mandel M
- et al.
was different. The increased risk of infection and severe COVID-19 outcomes seen as time elapsed since completion of the primary vaccination schedule was corrected by the booster, and this waning of vaccine effectiveness reflects existing reported work.
- Rosenberg ES
- Dorabawila V
- Easton D
- et al.
,
- Katikireddi SV
- Cerqueira-Silva T
- Vasileiou E
- et al.
,
- Stuart ASV
- Shaw RH
- Liu X
- et al.
- Hall V
- Foulkes S
- Insalata F
- et al.
,
- Manisty C
- Otter AD
- Treibel TA
- et al.
found that previous SARS-CoV-2 infection was associated with a reduced risk of severe COVID-19, there is a caveat that infection with different variants might not confer the same degree of protection, and the population-scale roll-out of booster vaccines has precluded assessment of previous immunity owing to logistical challenges, which suggests that boosting remains appropriate among individuals with previous SARS-CoV-2 infection for the time being. However, as further evidence accumulates, the risk of severe COVID-19 outcomes among individuals who were previously infected with SARS-CoV-2 virus should be reassessed.
- Wang L
- Davis PB
- Kaelber DC
- Volkow ND
- Xu R
- Levin EG
- Lustig Y
- Cohen C
- et al.
which showed that peak antibody responses were seen in the first month after vaccination but then declined almost four-fold over the following 10 weeks. Similarly, post-booster antibody responses have been shown to peak, but immune waning then occurs rapidly, with one study
- Regev-Yochay G
- Gonen T
- Gilboa M
- et al.
reporting a 5·5-fold decrease in peak antibody titre within 16 weeks. Because we did not have access to serological data within this study, we could not determine if individuals with specific clinical risk factors mounted a full immune response after a booster, but a previous study
- Kearns P
- Siebert S
- Gaskell C
- et al.
has reported suboptimal immunological responses across many of the groups identified in our analysis as being at increased risk of severe COVID-19 outcomes. Thus, there is a need for follow-on work to investigate risks of severe COVID-19 outcomes after booster in those who have been shown to mount a full immunological response.
Our findings indicate a range of demographic and clinical factors associated with increased clinical risk of severe COVID-19 outcomes despite booster vaccination and raise questions regarding future approaches to enhance protection. Increased clinical risk within older people is not unexpected and is likely to reflect underlying frailty, comorbidity, and immune senescence. Indeed, this pattern is seen with other respiratory viruses, despite the introduction of novel adjuvanted vaccine formulations. Immune senescence is a feature common to several risk groups and indicates that, despite strong immunogenicity, current COVID-19 vaccines cannot deliver equivalent protection to all individuals. Future approaches should aim to improve vaccine immunogenicity and involve a range of novel strategies, including variant-specific immunogenic agents, introduction of viral proteins in addition to spike, and the incorporation of immunodominant cellular epitopes. However, these approaches are unlikely to overcome immune suppression in the most vulnerable groups and for that reason additional approaches, such as administration of anti-spike monoclonal antibodies and antivirals, should also be considered.
These findings have been shared with JCVI and the Chief Medical Officers and Chief Scientific Advisers of the UK nations and are now being considered as the UK plans its autumn COVID-19 booster vaccine programme. This analysis has helped to generate timely insights that are now being used to help identify and prioritise individuals most likely to benefit from second vaccine boosters and COVID-19 therapeutics. Policy makers will not only need to consider this evidence (and any other evidence) on risk groups, but also the logistical aspects of administering booster doses to a substantial proportion of the UK’s population.
There is a need to investigate immunological responses to vaccination in those who have been identified as being at high risk after a first booster dose. Our plan is to continue to analyse data on uptake and impact of second dose boosters as the vaccine programme proceeds.
In summary, this UK-wide, population-based analysis has found that individuals who received their first booster vaccination were at reduced risk of COVID-19-related hospitalisation or death compared with those who had only completed their primary vaccination schedule. Older age, those with a higher number of comorbid conditions, and those with a range of specific underlying conditions were, however, found to be at increased risk of severe COVID-19 outcomes and might particularly benefit from additional, preferentially novel, COVID-19 boosters, pre-exposure prophylaxis, and COVID-19 therapeutics.
AS, CRS, CR, and LR conceived the original EAVE II study. AS conceived this study. UA and CMC led the writing of the paper and edited the final manuscript with help from AS, SB, ZG, and AA-L. SdL and MJ conceived how Research and Surveillance Centre data could support this study and are the guarantors of these data; JO conducted these analyses, JO; and SdL, MJ, and RSMT added the analysis on data from England to the paper. LP and DTB were responsible for data cleaning, and LP contributed to the analysis in Northern Ireland. UA accessed and verified the underlying data and is responsible for data cleaning and analysis in Scotland. SB accessed and verified the underlying data and is responsible for data cleaning and analysis in Wales. CR oversaw all the analyses. All authors contributed to the study design and all authors contributed to drafting the paper and revised the manuscript for important intellectual content. All authors have seen and approved the final text and gave final approval of the version to be published.
Declaration of interests
AS and CR are members of the Scottish Government Chief Medical Officer’s COVID-19 Advisory Group. AS is a member of the Scottish Government’s Standing Committee on Pandemic Preparedness, the UK Government’s New and Emerging Respiratory Virus Threats Advisory Group (known as NERVTAG) Risk Stratification Subgroup, the Department of Health and Social Care’s COVID-19 Therapeutics Modelling Group, and was a member of AstraZeneca’s COVID-19 Strategic Thrombocytopenia Taskforce. All AS’s roles are unfunded. CMC reports research funding from the Medical Research Council, Health Data Research UK, the National Institute for Health and Care Research, and the Scottish Chief Scientist Office. SVK was Co-Chair of the Scottish Government’s Expert Reference Group on COVID-19 and ethnicity and is a member of the SAGE subgroup on ethnicity. SVK acknowledges funding from an NRS Senior Clinical Fellowship (SCAF/15/02), the Medical Research Council (MC_UU_00022/2), and the Scottish Government Chief Scientist Office (SPHSU17). CR is a member of the Scientific Pandemic Influenza Group on Modelling, Medicines and Healthcare products Regulatory Agency Vaccine Benefit and Risk Working Group. SdL received funding through his university for vaccine-related research from AstraZeneca, GSK, Sanofi, Seqirus, and Takeda. He has been a member of advisory boards for AstraZeneca, Sanofi, and Seqirus, and is Director of the Research and Surveillance Centre. All other authors declare no competing interests.
Acknowledgments
This work was funded by the National Core Studies–Immunity group. This research is part of the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (grant ref MC_PC_20060), with support from the DaC-VaP-2 study also funded by UK Research and Innovation (grant ref MC_PC_20058). The study entitled “Use of national linked health care, serological data, and viral genomic data to identify and characterise post-third and -booster dose vaccine breakthroughs at a population level” is a partnership between the University of Edinburgh, Swansea University, Oxford University, Queen’s University of Belfast, University of St Andrews, and The Office for National Statistics. The authors would like to acknowledge all other project collaborators not involved in these analyses but who are contributing to wider discussions and preceding outputs. EAVE II is funded by the Medical Research Council (MR/R008345/1) with the support of BREATHE–The Health Data Research Hub for Respiratory Health (MC_PC_19004), which is funded through the UK Research and Innovation Industrial Strategy Challenge Fund and is delivered through Health Data Research UK. Additional support has been provided through Public Health Scotland and Scottish Government Director-General Health and Social Care. We thank Dave Kelly from Albasoft for his support with making primary care data available, and James Pickett, Wendy Inglis-Humphrey, Vicky Hammersley, Maria Georgiou, Laura Gonzalez Rienda, Pam McVeigh, Amanda Burridge, Sumedha Asnani-Chetal, and Afshin Dastafshan for their support with project management and administration. We acknowledge the support of the EAVE II Patient Advisory Group. We thank the patients and practice of the Research and Surveillance Centre who allow data sharing, and EMIS, TPP, Cegedim, and Wellbeing for help with pseudonymised data extraction. Rachel Byford and the ORCHID data team extracted these data, and Sneha N Anand project managed. We also acknowledge the help from Paul Moss and Samantha Lycett for in answering the reviews. The authors would like to acknowledge the help provided by the staff of the Honest Broker Service within the Business Services Organisation Northern Ireland (BSO). The Honest Broker Service is funded by the BSO and the Department of Health for Northern Ireland. The authors alone are responsible for the interpretation of the data and any views or opinions presented are solely those of the authors and do not necessarily represent those of the BSO.