SARS-CoV-2 breakthrough infections in vaccinated individuals: measurement, causes and impact

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Abstract

Breakthrough infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in fully vaccinated individuals are receiving intense scrutiny because of their importance in determining how long restrictions to control virus transmission will need to remain in place in highly vaccinated populations as well as in determining the need for additional vaccine doses or changes to the vaccine formulations and/or dosing intervals. Measurement of breakthrough infections is challenging outside of randomized, placebo-controlled, double-blind field trials. However, laboratory and observational studies are necessary to understand the impact of waning immunity, viral variants and other determinants of changing vaccine effectiveness against various levels of coronavirus disease 2019 (COVID-19) severity. Here, we describe the approaches being used to measure vaccine effectiveness and provide a synthesis of the burgeoning literature on the determinants of vaccine effectiveness and breakthrough rates. We argue that, rather than trying to tease apart the contributions of factors such as age, viral variants and time since vaccination, the rates of breakthrough infection are best seen as a consequence of the level of immunity at any moment in an individual, the variant to which that individual is exposed and the severity of disease being considered. We also address key open questions concerning the transition to endemicity, the potential need for altered vaccine formulations to track viral variants, the need to identify immune correlates of protection, and the public health challenges of using various tools to counter breakthrough infections, including boosters in an era of global vaccine shortages.

Abstract

Here, Lipsitch and colleagues assess the impact of breakthrough SARS-CoV-2 infections that occur in individuals who have been vaccinated against COVID-19. The authors explain how the rate of breakthrough infections can be measured, what the causes of these infections are and discuss other key questions that need to be considered in light of these infections.

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Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine

Fernando P Polack, Stephen J. Thomas, Nicholas R.E. Kitchin … (2023)

Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (Covid-19) have afflicted tens of millions of people in a worldwide pandemic. Safe and effective vaccines are needed urgently. Methods In an ongoing multinational, placebo-controlled, observer-blinded, pivotal efficacy trial, we randomly assigned persons 16 years of age or older in a 1:1 ratio to receive two doses, 21 days apart, of either placebo or the BNT162b2 vaccine candidate (30 μg per dose). BNT162b2 is a lipid nanoparticle–formulated, nucleoside-modified RNA vaccine that encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein. The primary end points were efficacy of the vaccine against laboratory-confirmed Covid-19 and safety. Results A total of 43,548 participants underwent randomization, of whom 43,448 received injections: 21,720 with BNT162b2 and 21,728 with placebo. There were 8 cases of Covid-19 with onset at least 7 days after the second dose among participants assigned to receive BNT162b2 and 162 cases among those assigned to placebo; BNT162b2 was 95% effective in preventing Covid-19 (95% credible interval, 90.3 to 97.6). Similar vaccine efficacy (generally 90 to 100%) was observed across subgroups defined by age, sex, race, ethnicity, baseline body-mass index, and the presence of coexisting conditions. Among 10 cases of severe Covid-19 with onset after the first dose, 9 occurred in placebo recipients and 1 in a BNT162b2 recipient. The safety profile of BNT162b2 was characterized by short-term, mild-to-moderate pain at the injection site, fatigue, and headache. The incidence of serious adverse events was low and was similar in the vaccine and placebo groups. Conclusions A two-dose regimen of BNT162b2 conferred 95% protection against Covid-19 in persons 16 years of age or older. Safety over a median of 2 months was similar to that of other viral vaccines. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728.)

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Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine

Lindsey Baden, Hana El Sahly, Brandon Essink … (2020)

Abstract Background Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle–encapsulated mRNA-based vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19. Methods This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infection or its complications were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 μg) or placebo 28 days apart. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with SARS-CoV-2. Results The trial enrolled 30,420 volunteers who were randomly assigned in a 1:1 ratio to receive either vaccine or placebo (15,210 participants in each group). More than 96% of participants received both injections, and 2.2% had evidence (serologic, virologic, or both) of SARS-CoV-2 infection at baseline. Symptomatic Covid-19 illness was confirmed in 185 participants in the placebo group (56.5 per 1000 person-years; 95% confidence interval [CI], 48.7 to 65.3) and in 11 participants in the mRNA-1273 group (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0); vaccine efficacy was 94.1% (95% CI, 89.3 to 96.8%; P<0.001). Efficacy was similar across key secondary analyses, including assessment 14 days after the first dose, analyses that included participants who had evidence of SARS-CoV-2 infection at baseline, and analyses in participants 65 years of age or older. Severe Covid-19 occurred in 30 participants, with one fatality; all 30 were in the placebo group. Moderate, transient reactogenicity after vaccination occurred more frequently in the mRNA-1273 group. Serious adverse events were rare, and the incidence was similar in the two groups. Conclusions The mRNA-1273 vaccine showed 94.1% efficacy at preventing Covid-19 illness, including severe disease. Aside from transient local and systemic reactions, no safety concerns were identified. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.)

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Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

Merryn Voysey, Sue Ann Costa Clemens, Shabir Madhi … (2022)

Background A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. Methods This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Findings Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; p interaction =0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. Interpretation ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. Funding UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D’Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.

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Contributors

Marc Lipsitch:

ORCID: http://orcid.org/0000-0003-1504-9213

mlipsitc@hsph.harvard.edu

Journal

Journal ID (nlm-ta): Nat Rev Immunol

Journal ID (iso-abbrev): Nat Rev Immunol

Title: Nature Reviews. Immunology

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 1474-1733

ISSN (Electronic): 1474-1741

Publication date (Electronic): 7 December 2021

Pages: 1-9

Affiliations

[1 ]GRID grid.38142.3c, ISNI 000000041936754X, Center for Communicable Disease Dynamics, Department of Epidemiology and Department of Immunology and Infectious Diseases, , Harvard T.H. Chan School of Public Health, ; Boston, MA USA

[2 ]GRID grid.59734.3c, ISNI 0000 0001 0670 2351, Department of Microbiology, , Icahn School of Medicine at Mount Sinai, ; New York, NY USA

[3 ]GRID grid.59734.3c, ISNI 0000 0001 0670 2351, Department of Pathology, Molecular and Cell-Based Medicine, , Icahn School of Medicine at Mount Sinai, ; New York, NY USA

[4 ]GRID grid.413795.d, ISNI 0000 0001 2107 2845, Infection Prevention & Control Unit, , Sheba Medical Center, ; Ramat-Gan, Israel

[5 ]GRID grid.12136.37, ISNI 0000 0004 1937 0546, Sackler School of Medicine, , Tel Aviv University, ; Tel Aviv, Israel

[6 ]GRID grid.413795.d, ISNI 0000 0001 2107 2845, The Central Virology Laboratory, Public Health Services, Ministry of Health, , Sheba Medical Center, ; Tel-Hashomer, Israel

[7 ]GRID grid.414553.2, ISNI 0000 0004 0575 3597, Clalit Research Institute, Innovation Division, , Clalit Health Services, ; Tel Aviv, Israel

[8 ]GRID grid.7489.2, ISNI 0000 0004 1937 0511, The School of Public Health, Faculty of Health Sciences, , Ben-Gurion University of the Negev, ; Be’er Sheva, Israel

Author information

Marc Lipsitch http://orcid.org/0000-0003-1504-9213

Florian Krammer http://orcid.org/0000-0003-4121-776X

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Publisher ID: 662

DOI: 10.1038/s41577-021-00662-4

PMC ID: 8649989

PubMed ID: 34876702

SO-VID: e9bcb5ca-3e0a-4898-a691-725cbfd70380

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This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

SARS-CoV-2 breakthrough infections in vaccinated individuals: measurement, causes and impact

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Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine

Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

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