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BNT162b2 induces SARS-CoV-2-neutralising antibodies and T cells in humans

Our take —

This study was available as a preprint and thus was not yet peer reviewed. In-depth characterization of vaccine-induced adaptive immune response is a critical step in developing our understanding of COVID-19 immunity. A very thorough evaluation of both the humoral and cellular immune responses elicited by the Pfizer/BioNTech BNT162b2 mRNA COVID-19 vaccine is presented here and provides largely encouraging data. However, the authors’ cursory assessment of the vaccine’s efficacy against the SARS-CoV-2 variants provides little reassurance, and should be largely disregarded. Although no evidence suggests that this vaccine’s efficacy would be reduced against any SARS-CoV-2 variant, the data presented here are insufficient to speak meaningfully to this topic.

Study design

Non-Randomized Trial

Study population and setting

This report presents data from a non-randomized open-label phase 1/2 trial evaluating humoral and cellular immune responses elicited in humans from the Pfizer/BioNTech BNT162b2 mRNA COVID-19 vaccine, which encodes the entirety of SARS-CoV-2 spike (S) protein. The total study population consisted of 48 white individuals (21 male, 27 female) aged 19-55 years, and each participant received two doses of the vaccine 21 days apart in a prime-boost regimen, with each dose containing 1, 10, 20, or 30 ug mRNA (NB: the approved Pfizer/BioNTech vaccine product currently in use utilizes a 30 ug dose of mRNA for each dose). Total SARS-CoV-2 specific antibody levels, neutralizing antibody titers, and cellular immune responses were measured at various timepoints. Additionally, sera from vaccinated participants were evaluated for neutralization of pseudotype vesicular stomatitis virus (VSV) expressing S from different SARS-CoV-2 variants. Participants were monitored for adverse reactions.

Summary of Main Findings

Increases in total SARS-CoV-2 specific antibody levels were observed following both the first and second doses of the vaccine, with particularly robust responses noted following the boost. All doses above 10 ug elicited a similar response, and levels two months post-boost amongst these doses exceeded those observed in convalescent COVID-19 patients. Neutralizing antibody titers increased substantially only following the boost, with a strong dose-dependent response observed for the 10, 20, and 30 ug doses (the 1 ug dose did not elicit an appreciable neutralizing antibody response). Two months following boost, neutralizing antibody titers amongst vaccinated participants also remained elevated above titers observed in convalescent COVID-19 patients. Neutralizing titers against the SARS-CoV-2 variants assessed using the pseudotype VSV assay were similar to those observed against the reference virus used, which was obtained from a COVID-19 patient in Washington state in January 2020 (SARS-CoV-2 USA_WA1/2020).

Measurable CD4+ and CD8+ T-cell responses were elicited against multiple epitopes throughout S (i.e., not just within the receptor binding domain) in 32/34 and 34/37 participants analyzed, respectively, and were not clearly dose-dependent above 10 ug. Specific epitopes recognized by vaccine-induced T-cells were also identified. A TH1-predominant response was reported and reduces concern regarding the possibility of vaccine-induced disease enhancement. Finally, the strength of the cellular immune response was noted to correlate with the strength of humoral immune response within individuals. Consistent with previous reports, no serious adverse reactions were recorded.

Study Strengths

This study provides an in-depth analysis (much of which is beyond the scope of this summary) of the adaptive immune response elicited by a COVID-19 vaccine currently in wide use. Particular attention is given to characterizing T-cell responses, providing data that will likely prove valuable for numerous ongoing and future studies. Additionally, SARS-CoV-2 specific antibody levels and neutralizing antibody titers are evaluated out to approximately 2 months (63 days) post-boost, extending our current scope of knowledge.

Limitations

A narrow demographic was utilized for this study, and did not include any elderly or non-white participants. The variant neutralization assay appears to be an afterthought and that aspect of the study is poorly designed. Evidently, the variants utilized each differed from the reference receptor binding domain sequence within S only by a single amino acid, and thus are not at all representative of the variants that are currently of concern in circulation (e.g., B.1.1.7, B.1.351, P.1), which generally harbor mutations at numerous sites within S. Additionally, it seems that there was approximately a log-fold increase in neutralization titers when using the pseudotype VSV assay. Furthermore, as the correlate(s) of protection remain unknown at this time, measurement of only neutralizing antibodies at a single time point for the variant analysis provides extremely limited information regarding overall vaccine efficacy in this context.

Value added

This study provides one of the most in-depth characterizations of COVID-19 vaccine-induced adaptive immune responses to date.

This review was posted on: 22 January 2021