Serum Neutralizing Activity Elicited by mRNA-1273 Vaccine — Preliminary Report

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Abstract

To the Editor: The mRNA-1273 vaccine against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) elicited high neutralizing-antibody titers in phase 1 trial participants 1,2 and has been shown to be highly efficacious in preventing symptomatic Covid-19 disease and severe disease. 3 The emergence of SARS-CoV-2 variants in the United Kingdom (the B.1.1.7 lineage), South Africa (the B.1.351 lineage), Brazil (the P.1 lineage), and California (the B.1.427/B.1.429 lineage) has led to concerns about increased transmission and the potential of these variants to circumvent immunity elicited by natural infection or vaccination. The recent identification in the United Kingdom of a B.1.1.7 variant that includes the E484K mutation (B.1.1.7+E484K) furthers these concerns. We assayed the neutralizing activity against recombinant vesicular stomatitis virus (rVSV)–based SARS-CoV-2 (a pseudovirus-based model) in serum samples obtained from eight participants in the phase 1 trial. The samples were obtained 1 week after the participants had received the second dose of mRNA-1273 vaccine. We tested pseudoviruses bearing the spike proteins from the original Wuhan-Hu-1 isolate, the D614G variant, and the B.1.1.7, B.1.351, P.1, B.1.427/B.1.429, B.1.1.7+E484K, and other variants (20E [EU1], 20A.EU2, N439K-D614G, and the mink cluster 5 variant that was first identified in Denmark). Both the full panel of mutations in S and a subset of mutations affecting the receptor-binding domain (RBD) region of the B.1.1.7 variant had no significant effect on neutralization by serum obtained from participants who had received the mRNA-1273 vaccine in the phase 1 trial (Figure 1A and 1B). In contrast, we observed a decrease in titers of neutralizing antibodies against the P.1 variant, the B.1.427/B.1.429 variant (versions 1 and 2), the B.1.1.7+E484K variant, and the B.1.351 variant as well as a subset of its mutations in the RBD. We detected reductions by a factor of between 2.3 and 6.4 in titers of neutralizing antibodies against this panel of variants (Figure 1C through 1I). The largest effect on neutralization, reduction by a factor of 6.4, was measured against the B.1.351 variant (Figure 1C and 1D). However, the geometric mean neutralizing titer against B.1.351 was 1:290, and all the serum samples fully neutralized the rVSV pseudovirus, albeit at relatively low dilutions (Fig. S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). The effect of the E484K mutation was observed by comparing neutralizing activity against the B.1.1.7 variant with neutralizing activity against the B.1.1.7+E484K variant. We found a significant reduction in neutralizing titers when the E484K mutation was present (Figure 1B and 1I). Using both rVSV and lentiviral neutralization assays, we observed a similar trend in serum samples obtained from macaque monkeys (Figs. S2 and S3). The rVSV-based pseudovirus neutralization assay was also used to assess the neutralizing activity of serum obtained from participants who had received the mRNA-1273 vaccine in the phase 1 trial against the full-length spike protein of the dominant strain in 2020 (D614G), as well as against 20E (EU1), 20A.EU2, N439K-D614G, and mink cluster 5 variants (Table S1). We observed levels of neutralization against these variants that were similar to those against the Wuhan-Hu-1 (D614) isolate (Fig. S4). Protection conferred by the mRNA-1273 vaccine against the P.1, B.1.427/B.1.429, and B.1.351 variants remains to be determined. Our findings underscore the importance of continued viral surveillance and evaluation of vaccine efficacy against new variants and may help to facilitate the establishment of correlates of protection in both nonhuman primates and humans.

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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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An mRNA Vaccine against SARS-CoV-2 — Preliminary Report

Lisa A Jackson, Evan J Anderson, Nadine G Rouphael … (2020)

Abstract Background The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 and spread globally, prompting an international effort to accelerate development of a vaccine. The candidate vaccine mRNA-1273 encodes the stabilized prefusion SARS-CoV-2 spike protein. Methods We conducted a phase 1, dose-escalation, open-label trial including 45 healthy adults, 18 to 55 years of age, who received two vaccinations, 28 days apart, with mRNA-1273 in a dose of 25 μg, 100 μg, or 250 μg. There were 15 participants in each dose group. Results After the first vaccination, antibody responses were higher with higher dose (day 29 enzyme-linked immunosorbent assay anti–S-2P antibody geometric mean titer [GMT], 40,227 in the 25-μg group, 109,209 in the 100-μg group, and 213,526 in the 250-μg group). After the second vaccination, the titers increased (day 57 GMT, 299,751, 782,719, and 1,192,154, respectively). After the second vaccination, serum-neutralizing activity was detected by two methods in all participants evaluated, with values generally similar to those in the upper half of the distribution of a panel of control convalescent serum specimens. Solicited adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site. Systemic adverse events were more common after the second vaccination, particularly with the highest dose, and three participants (21%) in the 250-μg dose group reported one or more severe adverse events. Conclusions The mRNA-1273 vaccine induced anti–SARS-CoV-2 immune responses in all participants, and no trial-limiting safety concerns were identified. These findings support further development of this vaccine. (Funded by the National Institute of Allergy and Infectious Diseases and others; mRNA-1273 ClinicalTrials.gov number, NCT04283461).

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Safety and Immunogenicity of SARS-CoV-2 mRNA-1273 Vaccine in Older Adults

Evan J Anderson, Nadine G Rouphael, Alicia T. Widge … (2020)

Abstract Background Testing of vaccine candidates to prevent infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in an older population is important, since increased incidences of illness and death from coronavirus disease 2019 (Covid-19) have been associated with an older age. Methods We conducted a phase 1, dose-escalation, open-label trial of a messenger RNA vaccine, mRNA-1273, which encodes the stabilized prefusion SARS-CoV-2 spike protein (S-2P) in healthy adults. The trial was expanded to include 40 older adults, who were stratified according to age (56 to 70 years or ≥71 years). All the participants were assigned sequentially to receive two doses of either 25 μg or 100 μg of vaccine administered 28 days apart. Results Solicited adverse events were predominantly mild or moderate in severity and most frequently included fatigue, chills, headache, myalgia, and pain at the injection site. Such adverse events were dose-dependent and were more common after the second immunization. Binding-antibody responses increased rapidly after the first immunization. By day 57, among the participants who received the 25-μg dose, the anti–S-2P geometric mean titer (GMT) was 323,945 among those between the ages of 56 and 70 years and 1,128,391 among those who were 71 years of age or older; among the participants who received the 100-μg dose, the GMT in the two age subgroups was 1,183,066 and 3,638,522, respectively. After the second immunization, serum neutralizing activity was detected in all the participants by multiple methods. Binding- and neutralizing-antibody responses appeared to be similar to those previously reported among vaccine recipients between the ages of 18 and 55 years and were above the median of a panel of controls who had donated convalescent serum. The vaccine elicited a strong CD4 cytokine response involving type 1 helper T cells. Conclusions In this small study involving older adults, adverse events associated with the mRNA-1273 vaccine were mainly mild or moderate. The 100-μg dose induced higher binding- and neutralizing-antibody titers than the 25-μg dose, which supports the use of the 100-μg dose in a phase 3 vaccine trial. (Funded by the National Institute of Allergy and Infectious Diseases and others; mRNA-1273 Study ClinicalTrials.gov number, NCT04283461.)