1. Administration of mRNA-1273 to rhesus macaques induced ACE2 binding inhibition and neutralizing activity that were orders of magnitude higher than was measured in specimens of human convalescent-phase serum.
2. No vaccine-related pathological changes were observed in lung tissue.
Evidence Rating Level: 2 (Good)
Study Rundown: As the Covid-19 pandemic continues to sweep the world, a number of vaccine approaches against SARS-CoV-2 are being investigated, including whole-inactivated and replication-defective viruses as well as subunit protein and nucleic acid vaccines. The majority of these candidates target the trimeric spike (S) protein responsible for ACE2 receptor binding and membrane fusion. mRNA-1273, for instance, is an encapsulated lipid nanoparticle that encodes the S glycoprotein in its prefusion conformation. This nucleoside-modified RNA vaccine has been shown to be tolerable and immunogenic through preliminary experiments in both mouse models and human subjects, raising the question of whether it could be used to limit respiratory infection in the intermediate system of nonhuman primates which would offer stronger implications for clinical translation. In this study, mRNA-1273 was administered at various sub-milligram dosages to rhesus macaques, which were then evaluated for over 2 months. Numerous beneficial effects were observed, including rapid activation of CD4 cells, viral neutralization through binding of multiple S protein domains, and effective protection against upper- and lower-airway infection. However, no reduction of viral replication in nasal tissue was noted at the lower dose, suggesting an avenue for further research into the effect of vaccines on transmission. While long-term studies aimed at determining the durability of immunity after vaccination are still needed, these findings serve as compelling evidence for the efficacy of mRNA-1273 against SARS-CoV-2.
Relevant Reading: An mRNA Vaccine against SARS-CoV-2 — Preliminary Report
In-Depth [animal study]: In this study examining the protective effect of mRNA-1273 in nonhuman primates, 12 rhesus macaques of each sex were stratified into groups of 3, with each member being randomly assigned in a 1:1:1 ratio to receive intramuscular injections of 10 μg of mRNA-1273, 100 μg of mRNA-1273, or phosphate-buffered saline (control) at the 0 and 4 week timepoints. IgG binding to the S protein was found to increase in a dose-dependent manner upon enzyme‑linked immunosorbent assay (ELISA), reaching areas under the curve of 8241 and 36,186 for the 10 μg and 100 μg groups, respectively, by 4 weeks after the second vaccination. Neutralizing activity followed the same trend, with reciprocal 50% inhibitory dilution (ID50) geometric mean titers (GMTs) of 103 and 1862 for the two groups. Both metrics were many fold higher than in convalescent-phase serum samples from 42 humans representing the full range of disease severity. Dose-dependent Th1 and interleukin-21 responses were also detected in half of the 10 μg group and all of the 100 μg group, but Th2 and CD8 remained low to undetectable. At 8 weeks, all subjects were challenged with a total of 7.6×105 plaque-forming units (PFU)—3 ml via the intratracheal route and 1 ml via the intranasal route (0.5 ml per nostril)—and then assessed for viral load and serum antibody levels two days later. Only 1 animal in each treatment group had detectable subgenomic RNA in bronchoalveolar‑lavage (BAL) fluid compared to all 8 in the control group; peak and total RNA levels over 7 days were also significantly lower in both treatment groups than the control group. No vaccine-associated immunohistopathologic changes in lung tissue were observed after 2 weeks.
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