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Assessing Durability of Vaccine Effect Following Blinded Crossover in COVID-19 Vaccine Efficacy Trials.

ABSTRACT: Several candidate vaccines to prevent COVID-19 disease have entered large-scale phase 3 placebo-controlled randomized clinical trials and some have demonstrated substantial short-term efficacy. Efficacious vaccines should, at some point, be offered to placebo participants, which will occur before long-term efficacy and safety are known. Following vaccination of the placebo group, we show that placebo-controlled vaccine efficacy can be derived by assuming the benefit of vaccination over time has the same profile for the original vaccine recipients and the placebo crossovers. This reconstruction allows estimation of both vaccine durability and potential vaccine-associated enhanced disease. Post-crossover estimates of vaccine efficacy can provide insights about durability, identify waning efficacy, and identify late enhancement of disease, but are less reliable estimates than those obtained by a standard trial where the placebo cohort is maintained. As vaccine efficacy estimates for post-crossover periods depend on prior vaccine efficacy estimates, longer pre-crossover periods with higher case counts provide better estimates of late vaccine efficacy. Further, open-label crossover may lead to riskier behavior in the immediate crossover period for the unblinded vaccine arm, confounding vaccine efficacy estimates for all post-crossover periods. We advocate blinded crossover and continued follow-up of trial participants to best assess vaccine durability and potential delayed enhancement of disease. This approach allows placebo recipients timely access to the vaccine when it would no longer be proper to maintain participants on placebo, yet still allows important insights about immunological and clinical effectiveness over time.

SUBMITTER: Follmann D

PROVIDER: S-EPMC7745130 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Assessing Durability of Vaccine Effect Following Blinded Crossover in COVID-19 Vaccine Efficacy Trials.

Follmann Dean D Fintzi Jonathan J Fay Michael P MP Janes Holly E HE Baden Lindsey L Sahly Hana El HE Fleming Thomas R TR Mehrotra Devan V DV Carpp Lindsay N LN Juraska Michal M Benkeser David D Donnell Deborah D Fong Youyi Y Han Shu S Hirsch Ian I Huang Ying Y Huang Yunda Y Hyrien Ollivier O Luedtke Alex A Carone Marco M Nason Martha M Vandebosch An A Zhou Honghong H Cho Iksung I Gabriel Erin E Kublin James G JG Cohen Myron S MS Corey Lawrence L Gilbert Peter B PB Neuzil Kathleen M KM

medRxiv : the preprint server for health sciences 20201214

<h4>Background</h4>Several candidate vaccines to prevent COVID-19 disease have entered large-scale phase 3 placebo-controlled randomized clinical trials and some have demonstrated substantial short-term efficacy. Efficacious vaccines should, at some point, be offered to placebo participants, which will occur before long-term efficacy and safety are known.<h4>Methods</h4>Following vaccination of the placebo group, we show that placebo-controlled vaccine efficacy can be derived by assuming the ben ...[more]

PMID: 33336213

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Project description:ImportanceAntibody responses elicited by current messenger RNA (mRNA) COVID-19 vaccines decline rapidly and require repeated boosting.ObjectiveTo evaluate the immunogenicity and durability of heterologous and homologous prime-boost regimens involving the adenovirus vector vaccine Ad26.COV2.S and the mRNA vaccine BNT162b2.Design, setting, and participantsIn this cohort study at a single clinical site in Boston, Massachusetts, 68 individuals who were vaccinated at least 6 months previously with 2 immunizations of BNT162b2 were boosted with either Ad26.COV2.S or BNT162b2. Enrollment of participants occurred from August 12, 2021, to October 25, 2021, and this study involved 4 months of follow-up. Data analysis was performed from November 2021 to February 2022.ExposuresParticipants who were previously vaccinated with BNT162b2 received a boost with either Ad26.COV2.S or BNT162b2.Main outcomes and measuresHumoral immune responses were assessed by neutralizing, binding, and functional antibody responses for 16 weeks following the boost. CD8+ and CD4+ T-cell responses were evaluated by intracellular cytokine staining assays.ResultsAmong 68 participants who were originally vaccinated with BNT162b2 and boosted with Ad26.COV2.S (41 participants; median [range] age, 36 [23-84] years) or BNT162b2 (27 participants; median [range] age, 35 [23-76] years), 56 participants (82%) were female, 7 (10%) were Asian, 4 (6%) were Black, 4 (6%) were Hispanic or Latino, 3 (4%) were more than 1 race, and 53 (78%) were White. Both vaccines were found to be associated with increased humoral and cellular immune responses, including against SARS-CoV-2 variants of concern. BNT162b2 boosting was associated with a rapid increase of Omicron neutralizing antibodies that peaked at a median (IQR) titer of 1018 (699-1646) at week 2 and declined by 6.9-fold to a median (IQR) titer of 148 (95-266) by week 16. Ad26.COV2.S boosting was associated with increased Omicron neutralizing antibodies titers that peaked at a median (IQR) of 859 (467-1838) week 4 and declined by 2.1-fold to a median (IQR) of 403 (208-1130) by week 16.Conclusions and relevanceHeterologous Ad26.COV2.S boosting was associated with durable humoral and cellular immune responses in individuals who originally received the BNT162b2 vaccine. These data suggest potential benefits of heterologous prime-boost vaccine regimens for SARS-CoV-2.

Dataset Information

Assessing Durability of Vaccine Effect Following Blinded Crossover in COVID-19 Vaccine Efficacy Trials.

Publications

Assessing Durability of Vaccine Effect Following Blinded Crossover in COVID-19 Vaccine Efficacy Trials.

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