DISCUSSION
infection, SARS-CoV-2 infection
INFECTION, VIRUS, SARS-COV-2 INFECTION
For participants in the COVE trial with no evidence of previous SARS-CoV-2 infection at baseline and who received two doses of mRNA-1273 vaccine, LV-MNAcross all analyses, evidence for correlates was stronger for nAbs measured by the PsV-based versus live virus–based neutralization assay, consistent with the findings of a nonhuman primate challenge study (Furthermore, in that analysis, estimated vaccine efficacy was near zero for vaccine recipients with undetectable live virus neutralization but was positive for vaccine recipients with undetectable PsV neutralization. Postvaccination PsV-nAb IDThe apparent limitation of the live virus neutralization assay may reflect the diversity of live virus assay designs. It may also reflect the replication capacity of SARS-CoV-2 in Vero-E6 cells derived from African green monkey epithelial cells. In contrast, the PsV assay was performed in human embryonic kidney 293 cells, a human cell line overexpressing angiotensin-converting enzyme–related carboxypeptidase (ACE2) (the primary cellular receptor for SARS-CoV-2). A live virus neutralization assay using human airway epithelial or lung epithelial cells may yield a better CoP. In addition, because the ancestral SARS-CoV-2 strain was used in the live virus neutralization assay, the use of a strain more closely representative of the circulating variant during the time of follow-up may also yield a better correlate. Consistent with this hypothesis, the D614G strain (used in the PsV neutralization assay) was the predominant variant during the trial. Another potential explanation is the greater technical variability in the live virus assay, such that correlate strength depends on assay precision (as also suggested by the better correlate with IDFrom the PsV assay, the IDMany of the strengths of this analysis are the same as those of our previous correlate analyses (Limitations of this study include that it evaluated short-term efficacy only against virus strains highly similar to the vaccine-insert strain; thus, this study is a “homologous antibody correlates study.” An additional limitation of this work is that this study evaluated one specific live virus neutralization assay, which differed from that studied in (Future work on the COVE study to further characterize immune CoPs of the mRNA-1273 vaccine will be to apply the binding and PsV neutralization assays to samples at 4 weeks after dose 3 and to study antibody marker measurements to Omicron strains as CoPs against COVID-19 caused by infection from the Omicron variants. These studies are planned to be conducted in SARS-CoV-2–naïve individuals with no evidence of SARS-CoV-2 infection at any time up to dose 3 and in SARS-CoV-2–nonnaïve individuals with evidence of SARS-CoV-2 infection after receiving the two-dose primary series and before dose 3. Given that the correlate analyses of COVE to date have been restricted to SARS-CoV-2–naïve individuals, COVID-19 endpoints by ancestral strain-like viruses, and antibodies to the ancestral strain, these future analyses should provide multiple insights relevant for guiding vaccine development and use in the contemporary context of the COVID-19 pandemic.