• An aluminum hydroxide:CpG adjuvant enhances protection elicited by a SARS-CoV-2 receptor binding domain vaccine in aged mice.

      Nanishi, Etsuro; Borriello, Francesco; O'Meara, Timothy R; McGrath, Marisa E; Saito, Yoshine; Haupt, Robert E; Seo, Hyuk-Soo; van Haren, Simon D; Cavazzoni, Cecilia B; Brook, Byron; et al. (American Association for the Advancement of Science, 2022-01-26)
      Global deployment of vaccines that can provide protection across several age groups is still urgently needed to end the COVID-19 pandemic, especially in low- and middle-income countries. Although vaccines against SARS-CoV-2 based on mRNA and adenoviral vector technologies have been rapidly developed, additional practical and scalable SARS-CoV-2 vaccines are required to meet global demand. Protein subunit vaccines formulated with appropriate adjuvants represent an approach to address this urgent need. The receptor binding domain (RBD) is a key target of SARS-CoV-2 neutralizing antibodies but is poorly immunogenic. We therefore compared pattern recognition receptor (PRR) agonists alone or formulated with aluminum hydroxide (AH) and benchmarked them against AS01B and AS03-like emulsion-based adjuvants for their potential to enhance RBD immunogenicity in young and aged mice. We found that an AH and CpG adjuvant formulation (AH:CpG) produced an 80-fold increase in anti-RBD neutralizing antibody titers in both age groups relative to AH alone and protected aged mice from the SARS-CoV-2 challenge. The AH:CpG-adjuvanted RBD vaccine elicited neutralizing antibodies against both wild-type SARS-CoV-2 and the B.1.351 (beta) variant at serum concentrations comparable to those induced by the licensed Pfizer-BioNTech BNT162b2 mRNA vaccine. AH:CpG induced similar cytokine and chemokine gene enrichment patterns in the draining lymph nodes of both young adult and aged mice and enhanced cytokine and chemokine production in human mononuclear cells of younger and older adults. These data support further development of AH:CpG-adjuvanted RBD as an affordable vaccine that may be effective across multiple age groups.
    • Antinucleocapsid Antibodies After SARS-CoV-2 Infection in the Blinded Phase of the Randomized, Placebo-Controlled mRNA-1273 COVID-19 Vaccine Efficacy Clinical Trial.

      Follmann, Dean; Janes, Holly E; Buhule, Olive D; Zhou, Honghong; Girard, Bethany; Marks, Kristen; Kotloff, Karen; Desjardins, Michaël; Corey, Lawrence; Neuzil, Kathleen M; et al. (American College of Physicians, 2022-07-05)
      Vaccination status should be considered when interpreting seroprevalence and seropositivity data based solely on anti-N Ab testing. Primary Funding source: National Institute of Allergy and Infectious Diseases of the National Institutes of Health.
    • A Deferred-Vaccination Design to Assess Durability of COVID-19 Vaccine Effect After the Placebo Group Is Vaccinated

      Follmann, Dean; Fintzi, Jonathan; Fay, Michael P; Janes, Holly E; Baden, Lindsey R; El Sahly, Hana M; Fleming, Thomas R; Mehrotra, Devan V; Carpp, Lindsay N; Juraska, Michal; et al. (American College of Physicians, 2021-04-13)
      Multiple candidate vaccines to prevent COVID-19 have entered large-scale phase 3 placebo-controlled randomized clinical trials, and several have demonstrated substantial short-term efficacy. At some point after demonstration of substantial efficacy, placebo recipients should be offered the efficacious vaccine from their trial, which will occur before longer-term efficacy and safety are known. The absence of a placebo group could compromise assessment of longer-term vaccine effects. However, by continuing follow-up after vaccination of the placebo group, this study shows that placebo-controlled vaccine efficacy can be mathematically derived by assuming that the benefit of vaccination over time has the same profile for the original vaccine recipients and the original placebo recipients after their vaccination. Although this derivation provides less precise estimates than would be obtained by a standard trial where the placebo group remains unvaccinated, this proposed approach allows estimation of longer-term effect, including durability of vaccine efficacy and whether the vaccine eventually becomes harmful for some. Deferred vaccination, if done open-label, may lead to riskier behavior in the unblinded original vaccine group, confounding estimates of long-term vaccine efficacy. Hence, deferred vaccination via blinded crossover, where the vaccine group receives placebo and vice versa, would be the preferred way to assess vaccine durability and potential delayed harm. Deferred vaccination allows placebo recipients timely access to the vaccine when it would no longer be proper to maintain them on placebo, yet still allows important insights about immunologic and clinical effectiveness over time.
    • Durability of Protection Against Symptomatic COVID-19 Among Participants of the mRNA-1273 SARS-CoV-2 Vaccine Trial.

      Lin, Dan-Yu; Baden, Lindsey R; El Sahly, Hana M; Essink, Brandon; Neuzil, Kathleen M; Corey, Lawrence; Miller, Jacqueline (American Medical Association, 2022-06-01)
    • Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine

      Baden, Lindsey R; El Sahly, Hana M; Essink, Brandon; Kotloff, Karen; Frey, Sharon; Novak, Rick; Diemert, David; Spector, Stephen A; Rouphael, Nadine; Creech, C Buddy; et al. (Massachusetts Medical Society, 2020-12-30)
      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.
    • Immune correlates analysis of the mRNA-1273 COVID-19 vaccine efficacy clinical 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; et al. (American Association for the Advancement of Science, 2021-11-23)
    • Phase 3 Trial of mRNA-1273 during the Delta-Variant Surge

      Baden, Lindsey R; El Sahly, Hana M; Essink, Brandon; Follmann, Dean; Neuzil, Kathleen M; August, Allison; Clouting, Heather; Fortier, Gabrielle; Deng, Weiping; Han, Shu; et al. (Massachusetts Medical Society, 2021-11-03)
    • SARS-CoV-2 Omicron Variant Neutralization after mRNA-1273 Booster Vaccination.

      Pajon, Rolando; Doria-Rose, Nicole A; Shen, Xiaoying; Schmidt, Stephen D; O'Dell, Sijy; McDanal, Charlene; Feng, Wenhong; Tong, Jin; Eaton, Amanda; Maglinao, Maha; et al. (Massachusetts Medical Society, 2022-01-26)