Todd, J.-P. | Search bioRxiv

bioRxiv2021

Evaluation of mRNA-1273 against SARS-CoV-2 B.1.351 Infection in Nonhuman Primates

BackgroundVaccine efficacy against the B.1.351 variant following mRNA-1273 vaccination in humans has not been determined. Nonhuman primates (NHP) are a useful model for demonstrating whether mRNA-1273 mediates protection against B.1.351. MethodsNonhuman primates received 30 or 100 {micro}g of mRNA-1273 as a prime-boost vaccine at 0 and 4 weeks, a single immunization of 30 {micro}g at week 0, or no vaccine. Antibody and T cell responses were assessed in blood, bronchioalveolar lavages (BAL), and nasal washes. Viral replication in BAL and nasal swabs were determined by qRT-PCR for sgRNA, and histopathology and viral antigen quantification were performed on lung tissue post-challenge. ResultsEight weeks post-boost, 100 {micro}g x2 of mRNA-1273 induced reciprocal ID50 neutralizing geometric mean titers against live SARS-CoV-2 D614G and B.1.351 of 3300 and 240, respectively, and 430 and 84 for the 30 {micro}g x2 group. There were no detectable neutralizing antibodies against B.1351 after the single immunization of 30 {micro}g. On day 2 following B.1.351 challenge, sgRNA in BAL was undetectable in 6 of 8 NHP that received 100 {micro}g x2 of mRNA-1273, and there was a [~]2-log reduction in sgRNA in NHP that received two doses of 30 {micro}g compared to controls. In nasal swabs, there was a 1-log10 reduction observed in the 100 {micro}g x2 group. There was limited inflammation or viral antigen in lungs of vaccinated NHP post-challenge. ConclusionsImmunization with two doses of mRNA-1273 achieves effective immunity that rapidly controls lower and upper airway viral replication against the B.1.351 variant in NHP.

immunology↗

bioRxiv2018

Epitope-based vaccine design yields fusion peptide-directed antibodies that neutralize diverse strains of HIV-1

A central goal of HIV-1-vaccine research is the elicitation of antibodies capable of neutralizing diverse primary isolates of HIV-1. Here we show that focusing the immune response to exposed N-terminal residues of the fusion peptide, a critical component of the viral entry machinery and the epitope of antibodies elicited by HIV-1 infection, through immunization with fusion peptide-coupled carriers and prefusion-stabilized envelope trimers, induces cross-clade neutralizing responses. In mice, these immunogens elicited monoclonal antibodies capable of neutralizing up to 31% of a cross-clade panel of 208 HIV-1 strains. Crystal and cryo-electron microscopy structures of these antibodies revealed fusion peptide-conformational diversity as a molecular explanation for the cross-clade neutralization. Immunization of guinea pigs and rhesus macaques induced similarly broad fusion peptide-directed neutralizing responses suggesting translatability. The N terminus of the HIV-1-fusion peptide is thus a promising target of vaccine efforts aimed at eliciting broadly neutralizing antibodies.

immunology↗