Public health impact of delaying second dose of BNT162b2 or mRNA-1273 covid-19 vaccine: simulation agent based modeling study

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Abstract

Objective

To estimate population health outcomes with delayed second dose versus standard schedule of SARS-CoV-2 mRNA vaccination.

Design

Simulation agent based modeling study.

Setting

Simulated population based on real world US county.

Participants

The simulation included 100 000 agents, with a representative distribution of demographics and occupations. Networks of contacts were established to simulate potentially infectious interactions though occupation, household, and random interactions.

Interventions

Simulation of standard covid-19 vaccination versus delayed second dose vaccination prioritizing the first dose. The simulation runs were replicated 10 times. Sensitivity analyses included first dose vaccine efficacy of 50%, 60%, 70%, 80%, and 90% after day 12 post-vaccination; vaccination rate of 0.1%, 0.3%, and 1% of population per day; assuming the vaccine prevents only symptoms but not asymptomatic spread (that is, non-sterilizing vaccine); and an alternative vaccination strategy that implements delayed second dose for people under 65 years of age, but not until all those above this age have been vaccinated.

Main outcome measures

Cumulative covid-19 mortality, cumulative SARS-CoV-2 infections, and cumulative hospital admissions due to covid-19 over 180 days.

Results

Over all simulation replications, the median cumulative mortality per 100 000 for standard dosing versus delayed second dose was 226 v 179, 233 v 207, and 235 v 236 for 90%, 80%, and 70% first dose efficacy, respectively. The delayed second dose strategy was optimal for vaccine efficacies at or above 80% and vaccination rates at or below 0.3% of the population per day, under both sterilizing and non-sterilizing vaccine assumptions, resulting in absolute cumulative mortality reductions between 26 and 47 per 100 000. The delayed second dose strategy for people under 65 performed consistently well under all vaccination rates tested.

Conclusions

A delayed second dose vaccination strategy, at least for people aged under 65, could result in reduced cumulative mortality under certain conditions.

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Most cited references 28

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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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Author and article information

Contributors

Santiago Romero-Brufau:

ORCID: https://orcid.org/0000-0002-9922-0083

Role: assistant professor of medicine and healthcare systems engineeringRole: instructor

Ayush Chopra:

ORCID: https://orcid.org/0000-0002-4070-4139

Role: masters student

Alex J Ryu:

ORCID: https://orcid.org/0000-0002-0138-5112

Role: assistant professor of medicine

Esma Gel: Role: associate professor

Ramesh Raskar:

ORCID: https://orcid.org/0000-0002-3254-3224

Role: associate professor

Walter Kremers:

ORCID: https://orcid.org/0000-0001-5714-3473

Role: associate professor biostatistics

Karen S Anderson:

ORCID: https://orcid.org/0000-0002-3870-5730

Role: professor

Jayakumar Subramanian:

ORCID: https://orcid.org/0000-0003-4621-2677

Role: senior research scientist

Balaji Krishnamurthy:

ORCID: https://orcid.org/0000-0002-0366-2427

Role: principal scientist and director

Abhishek Singh:

ORCID: https://orcid.org/0000-0003-0217-9801

Role: masters student

Kalyan Pasupathy:

ORCID: https://orcid.org/0000-0002-4760-2805

Role: associate professor of health care systems engineering

Yue Dong:

ORCID: https://orcid.org/0000-0002-1737-6536

Role: assistant professor

John C O’Horo:

ORCID: https://orcid.org/0000-0002-0880-4498

Role: associate professor of medicine

Walter R Wilson:

ORCID: https://orcid.org/0000-0003-2927-7313

Role: professor of medicine

Oscar Mitchell:

ORCID: https://orcid.org/0000-0002-5331-5562

Role: fellow, pulmonary and critical care medicine

Thomas C Kingsley:

ORCID: https://orcid.org/0000-0002-6212-8988

Role: assistant professor of medicine

Journal

Journal ID (nlm-ta): BMJ

Journal ID (iso-abbrev): BMJ

Journal ID (publisher-id): BMJ-US

Journal ID (hwp): bmj

Title: The BMJ

Publisher: BMJ Publishing Group Ltd.

ISSN (Print): 0959-8138

ISSN (Electronic): 1756-1833

Publication date Collection: 2021

Publication date (Electronic): 12 May 2021

Volume: 373

Electronic Location Identifier: n1087

Affiliations

[1 ]Department of Medicine, Mayo Clinic, Rochester, MN, USA

[2 ]Department of Biostatistics, Harvard T H Chan School of Public Health, Boston, MA, USA

[3 ]MIT Media Lab, Massachusetts Institute of Technology, Cambridge, MA, USA

[4 ]School of Life Sciences, Arizona State University, Phoenix, AZ, USA

[5 ]Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA

[6 ]Media and Data Science Research Lab, Adobe Inc Noidia, UP, India.

[7 ]Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, USA

[8 ]Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA

Author notes

Correspondence to: T C Kingsley Kingsley.Thomas@ 123456mayo.edu (or @TomCKingsley on Twitter)

Author information

Santiago Romero-Brufau https://orcid.org/0000-0002-9922-0083

Ayush Chopra https://orcid.org/0000-0002-4070-4139

Alex J Ryu https://orcid.org/0000-0002-0138-5112

Ramesh Raskar https://orcid.org/0000-0002-3254-3224

Walter Kremers https://orcid.org/0000-0001-5714-3473

Karen S Anderson https://orcid.org/0000-0002-3870-5730

Jayakumar Subramanian https://orcid.org/0000-0003-4621-2677

Balaji Krishnamurthy https://orcid.org/0000-0002-0366-2427

Abhishek Singh https://orcid.org/0000-0003-0217-9801

Kalyan Pasupathy https://orcid.org/0000-0002-4760-2805

Yue Dong https://orcid.org/0000-0002-1737-6536

John C O’Horo https://orcid.org/0000-0002-0880-4498

Walter R Wilson https://orcid.org/0000-0003-2927-7313

Oscar Mitchell https://orcid.org/0000-0002-5331-5562

Thomas C Kingsley https://orcid.org/0000-0002-6212-8988

Article

Publisher ID: roms065061

DOI: 10.1136/bmj.n1087

PMC ID: 8114182

PubMed ID: 33980718

SO-VID: e82789b8-79ff-4219-b4dc-907d1a1d6569

License:

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

Public health impact of delaying second dose of BNT162b2 or mRNA-1273 covid-19 vaccine: simulation agent based modeling study

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Abstract

Objective

Design

Setting

Participants

Interventions

Main outcome measures

Results

Conclusions

Related collections

Novel Coronavirus Disease COVID-19

Most cited references 28

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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