key: cord-0703309-fquzwsiu authors: Naranbhai, Vivek; Garcia-Beltran, Wilfredo F; Chang, Christina C; Mairena, Cristhian Berrios; Thierauf, Julia C; Kirkpatrick, Grace; Onozato, Maristela L; Cheng, Ju; St. Denis, Kerri J; Lam, Evan C; Kaseke, Clarety; Tano-Menka, Rhoda; Yang, Diane; Pavlovic, Maia; Yang, Wendy; Kui, Alexander; Miller, Tyler E; Astudillo, Michael G; Cahill, Jennifer E; Dighe, Anand S; Gregory, David J; Poznansky, Mark C; Gaiha, Gaurav D; Balazs, Alejandro B; Iafrate, A John title: Comparative immunogenicity and effectiveness of mRNA-1273, BNT162b2 and Ad26.COV2.S COVID-19 vaccines date: 2021-12-09 journal: J Infect Dis DOI: 10.1093/infdis/jiab593 sha: 1e3ad8b25e61da2645ccfd9b23dfacf000dbe58a doc_id: 703309 cord_uid: fquzwsiu BACKGROUND: Understanding immunogenicity and effectiveness of SARS-CoV-2 vaccines is critical to guide rational use. METHODS: We compared the immunogenicity of mRNA-1273, BNT-162b2 or Ad26.COV2.S in healthy ambulatory adults in Massachusetts, USA. To correlate immunogenicity with effectiveness of the three vaccines, we performed an inverse-variance meta-analysis of population level effectiveness from public health reports in >40 million individuals. RESULTS: A single dose of either mRNA vaccine yielded comparable antibody and neutralization titers to convalescent individuals. Ad26.COV2.S yielded lower antibody concentrations and frequently undetectable neutralization titers. Bulk and cytotoxic T-cell responses were higher in mRNA1273 and BNT162b2 than Ad26.COV2.S recipients. Regardless of vaccine, <50% of vaccinees demonstrated CD8+ T-cell responses. Antibody concentrations and neutralization titers increased comparably after the first dose of either vaccine, and further in recipients of a second dose. Prior infection was associated with high antibody concentrations and neutralization even after a single dose and regardless of vaccine. Neutralization of beta, gamma and delta strains were poorer regardless of vaccine. In meta-analysis, relative to mRNA1273 the effectiveness of BNT162b2 was lower against infection and hospitalization; and Ad26COV2.S was lower against infection, hospitalization and death. CONCLUSIONS: Variation in the immunogenicity correlates with variable effectiveness of the three FDA EUA vaccines deployed in the USA. Prophylactic vaccines against SARS-CoV-2 are being deployed globally to combat the COVID-19 pandemic. A burgeoning body of evidence links the immunogenicity of the different vaccines to the degree of protection from infection or disease, although a precise correlate has not been agreed upon and studies of direct comparisons of vaccines are limited. Vaccination with mRNA-1273 [1] (100ug, Moderna), BNT162b2 [2] (30ug, Pfizer) and Ad26.COV2.S [3] (5×10 10 viral particles, Johnson & Johnson/Janssen) were each shown to be efficacious in reducing the risk of severe disease and infection in randomized clinical trials [1] [2] [3] , and have received Emergency Use Authorization(EUA) or full approval from the United States FDA. All three vaccines encode a largely similar SARS CoV-2 spike protein homologous to the SARS-CoV-2 strain isolated in Wuhan(China) but differ in dose and mechanism of delivery(mRNA vs. adenovirus vectored). Scale-up of vaccination in the general population may plausibly result in outcomes different to the original trials because of broader inclusion in the real world, the evolution of viral variants and potential variation in vaccine production. Immunogenicity analyses nested within the randomized trials of several vaccines have consistently demonstrated a quantitative association between anti-spike antibodies and/or neutralization titers and infection outcomes [4] [5] [6] [7] . In animal models, experimental transfer of antibodies protects from infection [8] [9] [10] and in human randomized controlled-trials, prophylactic administration of neutralizing antibodies reduces incidence of clinical COVID-19 [11, 12] . However, there is no consensus between vaccine manufacturers on the immune assays to employ, nor in the details of similar assays, for example which viral variant to assess neutralization against. There are few data regarding the comparative immunogenicity of these vaccines, except for indirect inferences from publicly available trial data from manufacturers [13] [14] [15] and small recent studies [13] . These factors collectively justify direct comparisons between vaccines in real world settings using consistent methods. Such studies may provide data to base decisions regarding which vaccine to deploy, and timing of additional 'booster' doses. We compared the immunogenicity of mRNA1273, BNT162b2 and Ad26.COV2.S during the first months following their deployment in the pandemic in the USA. We found a distinct hierarchy in humoral and cellular immunity, including towards currently circulating viral variants. Moreover, we find that this hierarchy is mirrored by variation in population scale effectiveness. A c c e p t e d M a n u s c r i p t 4 Use of human samples was approved by Partners Institutional Review Board(protocol 2020P001081 and 2020P002274). Consenting adults in Chelsea, Massachusetts were enrolled in a study of antibody responses and sampled in August 2020 and/or early 2021(March or April 2021). Data in this study are also derived from previously reported cohorts of healthy adults who had received vaccination and enrolled in a COVID vaccine biobanking study. Demographic data, information regarding prior SARS CoV-2 testing, symptoms, and exposure was collected as was vaccine related information. Pre-pandemic serum samples were obtained from the clinical laboratories at Massachusetts General Hospital(MGH) as previously described [17] . We grouped patients by time post vaccination using a 7 day window to capture the expected kinetics of antibody production after vaccination. Individuals who had received a single dose of vaccination >=7 days prior(or had received a second dose less than 7 days prior) were analyzed as one-dose recipients; those who had received two doses >=7 days prior were analyzed as two-dose recipients. Anti-spike and anti-nucleocapsid antibodies were measured with the Roche Elecys assay. Additional measurement of receptor-binding domain(RBD) antibodies was performed with a customized ELISA assay. Serum neutralization was measured using an extensively validated SARS-CoV-2 pseudovirus neutralization assay [14] . Interferon gamma(IFN-γ) ELISpot assays were performed as previously described [15] We were female. We compared immune responses according to prior infection, and vaccination type and dose and adjusted for age, sex and duration (detailed in Supplementary Table 1) after vaccination in all analyses. We assessed total IgG/M/A binding antibody levels against the SARS-CoV-2 spike protein(Roche Elecsys Anti-SARS-CoV-2 S), and found substantial variation in antibody concentrations depending on prior infection, vaccine type and vaccine dose (Figure 1A , summarized in a multivariate regression model in Supplementary with prior infection who were vaccinated had ~2 log 10 IU/ml higher antibody concentrations than convalescent individuals regardless of vaccine type, even after a single dose. We next sought to confirm these results using orthogonal assays. In an independent, validated total immunoglobulin G, M and A (IgG/M/A) or IgG ELISA, measurement of receptor binding domain(RBD) binding antibodies confirmed the differences above; and IgM and IgA responses were low( Figure S1 ). Further measurement of IgG against RBDmultimers also confirmed these findings( Figure S2) . Control experiments revealed that IgG responses against equivalent RBD-multimers of less pathogenic, common coronaviruses OCU43 and HKU1 were comparable between groups supporting the specificity of these findings, and controlling for any sample collection or storage artifacts between recipients of the three vaccines( Figure S3 ). We assessed the ability of serum from participants to neutralize SARS-CoV-2 in using a well-characterized assay [14, 16] , a strain that has been noted to be more easily neutralized [18] . We introduced the Victoria strain-associated S247R mutation into the SARS CoV-2 Wuhan isolate used in this study. Sera from vaccine recipients demonstrated higher neutralization titers against this S247R-containing variant than the original Wuhan strain A c c e p t e d M a n u s c r i p t regardless of vaccine administered( Figure S4 ). Therefore differences in the described neutralization seen in this study vs. the Ad26.COV2.S trials may be partially accounted for by use of the S247R viral variant in prior studies. Variants neutralization for all strains, as most individuals had neutralization that was not measurable. We hypothesized that the observed relative differences in immunogenicity between the three studied vaccines may correlate with their relative clinical effectiveness against infection and severe disease(hospitalization and/or death) at the population-level. In randomized-clinical trials, performed prior to heterologous variants rising to dominate the pandemic, and conducted largely among younger adults without major comorbidities, the primary end-point efficacy was 94.1% for mRNA1273 [1] , 94.6% for BNT162b2 [2] and 66.1% for Ad26.COV2.S [3] . However, the differences between these studies with regard to study participant characteristics, study endpoints(severity of disease and onset relative to vaccination), the prevalence of viral variants and other factors make direct comparisons between vaccines difficult. We systematically searched for reports of comparative effectiveness, and performed a fixed-effects meta-analysis( Figure 5) . We identified five sub- We Among individuals with prior infection, mRNA vaccination conferred higher antibody concentration titers. This supports recent data suggesting a single dose of mRNA vaccine in seropositive convalescent patients elicits comparable antibody titers to seronegative individuals who receive two doses of mRNA vaccine [19] . However we extend these findings by showing that this trend applies to Ad26.COV2.S and is confirmed for all three vaccines with neutralization titers regardless of vaccine type and whether a second dose was given. These findings may explain why vaccination in the setting of prior infection appears to be associated with enhanced protection [20] . In settings with limited vaccine supply, consideration to prioritizing individuals without prior infection may be warranted. We found differences in the immunogenicity and effectiveness of the three FDA EUA vaccines in the USA. The higher immunogenicity and significantly enhanced effectiveness of mRNA1273 compared with BNT162b2 may be due to the roughly 3.3-fold higher dose administered in the mRNA1273 regimen. Surprisingly, we observed sustained lower immunogenicity of the Ad26.COV2.S vaccine by multiple measures. These findings contrast with small studies from the manufacturer which employed a viral variant that was more readily neutralized in vitro than ancestral SARS CoV-2 here and in prior studies but concur with recent studies by Tada and colleagues [13] . These data further highlight the need for immunogenicity assessment using consistent assays to permit comparisons. Consistent with the lower efficacy in trials, breakthrough infection, hospitalization and death rates after cytotoxic T-cells in this, and other studies [21, 22] , makes this specific measure unlikely to be a universal mechanism of protection from severe disease in vaccinated individuals. Several important limitations of this study are worth highlighting. First, the immunogenicity studies were focused on largely healthy individuals. Further study in the particular risk groups may be warranted. Secondly, we did not measure other features of the immune system such as non-neutralizing antibodies [23] Foundation. The authors declare no conflicts of interest related to this work. neutralization of the relevant SARS-CoV-2 wildtype pseudovirus entry into ACE2 expressing 293T cells) is shown for each donor against the SARS CoV-2 wild type(Wuhan) strain, the beta gamma and delta viral variants and SARS CoV-2. The geometric mean titer, foldchange relative to neutralization of wild-type, and proportion above the lower limit of detection(LLOD denoted by horizontal dotted line at pNT50=12), and degree of statistical evidence relative to wild-type is shown above each group. Non-parametric(Friedman) test pvalues relative to wild-type are denoted as ns not significant, * p<0.05, ** p<0.01, *** p<0.001. For each group the horizontal line denotes the geometric mean titer, and whiskers extend to 95% confidence interval. 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