Immune Correlates Analysis of the mRNA-1273 COVID-19 Vaccine Efficacy Trial

Gilbert, Peter B.; Montefiori, David C.; McDermott, Adrian B.; Fong, Youyi; Benkeser, David; Deng, Weiping; Zhou, Honghong; Houchens, Christopher R.; Martins, Karen; Jayashankar, Lakshmi; Castellino, Flora; Flach, Britta; Lin, Bob C.; O’Connell, Sarah; McDanal, Charlene; Eaton, Amanda; Sarzotti‐Kelsoe, Marcella; Lu, Yiwen; Yu, Chenchen; Borate, Bhavesh; Laan, Lars W. P. van der; Hejazi, Nima S.; Huynh, Chuong; Miller, Jacqueline M.; Sahly, Hana M. El; Baden, Lindsey R.; Baron, Mira; Cruz, Luis de la; Gay, Cynthia L.; Kalams, Spyros A.; Kelley, Colleen F.; Kutner, Mark E; Andrasik, Michele P.; Kublin, James G.; Corey, Lawrence; Neuzil, Kathleen M.; Carpp, Lindsay N.; Pajón, Rolando; Follmann, Dean; Donis, Ruben O.; Koup, Richard A.

doi:10.1101/2021.08.09.21261290

Cited by 146 publications

(192 citation statements)

References 41 publications

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“…Overall, only the S-RBD-ELISA provided a satisfactory quantitative correlation, in the same ballpark as others found, with quite comparable assay formats such as the Euroimmun ELISA [3] or in house S-RBD-CLIA tests [37]. Consequently, the S-(RBD)-ELISA formats such as, e.g., our in-house assay or the commercially available Euroimmunor Diasorin-tests are, amongst the analyzed tests, best suited to predict neutralization capacity and thus possibly for protection from infection or disease.…”

Section: Discussionsupporting

confidence: 63%

Spectrum Bias and Individual Strengths of SARS-CoV-2 Serological Tests—A Population-Based Evaluation

et al. 2021

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Antibody testing for determining the SARS-CoV-2 serostatus was rapidly introduced in early 2020 and since then has been gaining special emphasis regarding correlates of protection. With limited access to representative samples with known SARS-CoV-2 infection status during the initial period of test development and validation, spectrum bias has to be considered when moving from a “test establishment setting” to population-based settings, in which antibody testing is currently implemented. To provide insights into the presence and magnitude of spectrum bias and to estimate performance measures of antibody testing in a population-based environment, we compared SARS-CoV-2 neutralization to a battery of serological tests and latent class analyses (LCA) in a subgroup (n = 856) of the larger population based TiKoCo-19 cohort (n = 4185). Regarding spectrum bias, we could proof notable differences in test sensitivities and specificities when moving to a population-based setting, with larger effects visible in earlier registered tests. While in the population-based setting the two Roche ELECSYS anti-SARS-CoV-2 tests outperformed every other test and even LCA regarding sensitivity and specificity in dichotomous testing, they didn’t provide satisfying quantitative correlation with neutralization capacity. In contrast, our in-house anti SARS-CoV-2-Spike receptor binding domain (RBD) IgG-ELISA (enzyme-linked-immunosorbant assay) though inferior in dichotomous testing, provided satisfactory quantitative correlation and may thus represent a better correlate of protection. In summary, all tests, led by the two Roche tests, provided sufficient accuracy for dichotomous identification of neutralizing sera, with increasing spectrum bias visible in earlier registered tests, while the majority of tests, except the RBD-ELISA, didn’t provide satisfactory quantitative correlations.

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Section: Discussionsupporting

confidence: 63%

Spectrum Bias and Individual Strengths of SARS-CoV-2 Serological Tests—A Population-Based Evaluation

et al. 2021

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“…While the optimal timing of a third dose has not been established, the data from this trial provides important information to address the need for third booster dose in case of waning vaccine effectiveness. Although neutralizing antibody responses have been correlated to reduction of risk for breakthrough COVID-19 disease, 37 a threshold of protection has not been defined for the Wuhan-1 or Delta variants. Also, this study did not examine variant-specific booster vaccines or immune responses to variants of concern other than for Delta.…”

Section: Discussionmentioning

confidence: 99%

Immune Memory Response After a Booster Injection of mRNA-1273 for Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2)

Chu

Montefiori²,

Huang

et al. 2021

Preprint

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Rising breakthrough infections of coronavirus-2 (SARS-CoV-2) in previously immunized individuals has raised concerns for a potential booster to combat suspected waning immunity and new variants. In this study, participants immunized 6-8 months earlier with a primary series of two doses of 50 or 100 μg of mRNA-1273 were administered a booster injection of 50 μg of mRNA-1273. Neutralizing antibody levels at one month after the booster were 1.7-fold higher than those one-month post primary series second injection meeting the prespecified criteria for noninferiority, and indicating an immune memory response. The reactogenicity after the booster dose was similar to that after the second dose in the primary series of two doses of mRNA-1273 (50 or 100 μg) with no serious adverse events reported in the one-month follow-up period. These results demonstrate that a booster injection of mRNA-1273 in previously immunized individuals stimulated an immune response greater than the primary vaccination series.

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“…mRNA vaccines encoding a stabilized version of the full-length SARS-CoV-2 Spike protein are being widely administered and clinical trial data demonstrate up to 95% efficacy in preventing symptomatic COVID-19 ( 2, 3 ). These vaccines induce potent humoral immune responses, with neutralizing antibody titers emerging as a correlate of protection ( 4–6 ). Current evidence suggests that circulating antibodies persist for at least 6 months post-vaccination ( 7 ), though there is some decay from peak levels achieved after the second dose.…”

Section: Introductionmentioning

confidence: 99%

mRNA Vaccination Induces Durable Immune Memory to SARS-CoV-2 with Continued Evolution to Variants of Concern

Goel

Painter

Apostolidis

et al. 2021

Preprint

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SARS-CoV-2 mRNA vaccines have shown remarkable efficacy, especially in preventing severe illness and hospitalization. However, the emergence of several variants of concern and reports of declining antibody levels have raised uncertainty about the durability of immune memory following vaccination. In this study, we longitudinally profiled both antibody and cellular immune responses in SARS-CoV-2 naive and recovered individuals from pre-vaccine baseline to 6 months post-mRNA vaccination. Antibody and neutralizing titers decayed from peak levels but remained detectable in all subjects at 6 months post-vaccination. Functional memory B cell responses, including those specific for the receptor binding domain (RBD) of the Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617.2) variants, were also efficiently generated by mRNA vaccination and continued to increase in frequency between 3 and 6 months post-vaccination. Notably, most memory B cells induced by mRNA vaccines were capable of cross-binding variants of concern, and B cell receptor sequencing revealed significantly more hypermutation in these RBD variant-binding clones compared to clones that exclusively bound wild-type RBD. Moreover, the percent of variant cross-binding memory B cells was higher in vaccinees than individuals who recovered from mild COVID-19. mRNA vaccination also generated antigen-specific CD8+ T cells and durable memory CD4+ T cells in most individuals, with early CD4+ T cell responses correlating with humoral immunity at later timepoints. These findings demonstrate robust, multi-component humoral and cellular immune memory to SARS-CoV-2 and current variants of concern for at least 6 months after mRNA vaccination. Finally, we observed that boosting of pre-existing immunity with mRNA vaccination in SARS-CoV-2 recovered individuals primarily increased antibody responses in the short-term without significantly altering antibody decay rates or long-term B and T cell memory. Together, this study provides insights into the generation and evolution of vaccine-induced immunity to SARS-CoV-2, including variants of concern, and has implications for future booster strategies.

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Immune Correlates Analysis of the mRNA-1273 COVID-19 Vaccine Efficacy Trial

Cited by 146 publications

References 41 publications

Spectrum Bias and Individual Strengths of SARS-CoV-2 Serological Tests—A Population-Based Evaluation

Spectrum Bias and Individual Strengths of SARS-CoV-2 Serological Tests—A Population-Based Evaluation

Immune Memory Response After a Booster Injection of mRNA-1273 for Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2)

mRNA Vaccination Induces Durable Immune Memory to SARS-CoV-2 with Continued Evolution to Variants of Concern

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