The global COVID-19 pandemic caused by the SARS-CoV-2 virus has made the development of a vaccine a top biomedical priority. In this study, we developed a series of DNA vaccine candidates expressing different forms of the SARS-CoV-2 Spike (S) protein and evaluated them in 35 rhesus macaques. Vaccinated animals developed humoral and cellular immune responses, including neutralizing antibody titers comparable to those found in convalescent humans and macaques infected with SARS-CoV-2. Following vaccination, all animals were challenged with SARS-CoV-2, and the vaccine encoding the full-length S protein resulted in >3.1 and >3.7 log10 reductions in median viral loads in bronchoalveolar lavage and nasal mucosa, respectively, as compared with sham controls. Vaccine-elicited neutralizing antibody titers correlated with protective efficacy, suggesting an immune correlate of protection. These data demonstrate vaccine protection against SARS-CoV-2 in nonhuman primates.

Recent studies have reported protective efficacy of both natural immunity 1 and vaccine-induced immunity 2 – 7 against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenge in rhesus macaques. However, the importance of humoral and cellular immunity for protection against SARS-CoV-2 infection remains to be determined. Here we show that adoptive transfer of purified IgG from convalescent macaques protects naïve recipient rhesus macaques against SARS-CoV-2 challenge in a dose dependent fashion. Depletion of CD8+ T cells in convalescent animals partially abrogated the protective efficacy of natural immunity against SARS-CoV-2 re-challenge, suggesting the importance of cellular immunity in the context of waning or subprotective antibody titers. These data demonstrate that relatively low antibody titers are sufficient for protection against SARS-CoV-2 in rhesus macaques, and that cellular immune responses may also contribute to protection if antibody responses are suboptimal. We also show that higher antibody titers are required for therapy of SARS-CoV-2 infection in macaques. These findings have important implications for the development of SARS-CoV-2 vaccines and immune-based therapeutics.

An understanding of protective immunity to SARS-CoV-2 is critical for vaccine and public health strategies aimed at ending the global COVID-19 pandemic. A key unanswered question is whether infection with SARS-CoV-2 results in protective immunity against re-exposure. We developed a rhesus macaque model of SARS-CoV-2 infection and observed that macaques had high viral loads in the upper and lower respiratory tract, humoral and cellular immune responses, and pathologic evidence of viral pneumonia. Following initial viral clearance, animals were rechallenged with SARS-CoV-2 and showed 5 log10 reductions in median viral loads in bronchoalveolar lavage and nasal mucosa compared with primary infection. Anamnestic immune responses following rechallenge suggested that protection was mediated by immunologic control. These data show that SARS-CoV-2 infection induced protective immunity against re-exposure in nonhuman primates.

A safe and effective vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may be required to end the coronavirus disease 2019 (COVID-19) pandemic 1 – 8 . For global deployment and pandemic control, a vaccine that requires only a single immunization would be optimal. Here we show the immunogenicity and protective efficacy of a single dose of adenovirus serotype 26 (Ad26) vector-based vaccines expressing the SARS-CoV-2 spike (S) protein in nonhuman primates. 52 rhesus macaques were immunized with Ad26 vectors encoding S variants or sham control and were challenged with SARS-CoV-2 by the intranasal and intratracheal routes 9 , 10 . The optimal Ad26 vaccine induced robust neutralizing antibody responses and provided complete or near-complete protection in bronchoalveolar lavage and nasal swabs following SARS-CoV-2 challenge. Vaccine-elicited neutralizing antibody titers correlated with protective efficacy, suggesting an immune correlate of protection. These data demonstrate robust single-shot vaccine protection against SARS-CoV-2 in nonhuman primates. The optimal Ad26 vector-based vaccine for SARS-CoV-2, termed Ad26.COV2.S, is currently being evaluated in clinical trials.

The recent novel coronavirus disease (COVID-19) outbreak, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is seeing a rapid increase in infected patients worldwide. The host immune response to SARS-CoV-2 appears to play a critical role in disease pathogenesis and clinical manifestations. SARS-CoV-2 not only activates antiviral immune responses, but can also cause uncontrolled inflammatory responses characterized by marked pro-inflammatory cytokine release in patients with severe COVID-19, leading to lymphopenia, lymphocyte dysfunction, and granulocyte and monocyte abnormalities. These SARS-CoV-2-induced immune abnormalities may lead to infections by microorganisms, septic shock, and severe multiple organ dysfunction. Therefore, mechanisms underlying immune abnormalities in patients with COVID-19 must be elucidated to guide clinical management of the disease. Moreover, rational management of the immune responses to SARS-CoV-2, which includes enhancing anti-viral immunity while inhibiting systemic inflammation, may be key to successful treatment. In this review, we discuss the immunopathology of COVID-19, its potential mechanisms, and clinical implications to aid the development of new therapeutic strategies against COVID-19.