SARS-CoV-2 vaccines based on the ancestral Wuhan-Hu-1 Spike (S) protein have been shown to be effective in preventing severe COVID-19, hospitalization, and death. The evolution of SARS-CoV-2 variants of concern (VoC) exhibiting increasing genetic distance from Wuhan-Hu-1, such as Omicron BA.1 and its subvariants, is troubling. This genetic distance affects the receptor binding domain of the S glycoprotein, the primary target of neutralizing antibodies, resulting in decreased neutralization capacity for antibodies raised against prior variants. Booster immunization with Wuhan-Hu-1 based vaccinations has been shown to augment Omicron-specific neutralizing antibodies, but these boosters elicited lower levels of neutralizing antibodies against VoC. Targeting the S protein of these new VoC has the potential to increase the efficacy of the vaccine. To that end, Solforosi et al sought to elucidate the immunogenicity and efficacy of booster vaccination with Ad26.COV2.S (Wuhan-Hu-1 based vaccine), Ad26.COV2.S.529 (an experimental vaccine based on the Omicron BA.1 spike) or a 1:1 combination of the two in non-human primates (NHP) that had been previously immunized with Ad26.COV2.S.  

Adult rhesus macaques were previously immunized with Ad26.COV2.S and assigned to four groups by a randomized stratification system. One group received Ad26.COV2.S, one group received Ad26.COV2.S.529, one group received a combination of the two vaccines and one group received a sham saline injection. An additional fifth group were administered sham saline injections at both time points. A final sixth group initially received a sham saline injection and was boosted with Ad26.COV2.S.529 to study the efficacy of the experimental vaccine. Blood samples were collected before the booster and at weeks one, two, four, and six after booster administration to measure binding and neutralizing antibodies. At week six after booster administration, all animals were challenged with SARS-CoV-2 Omicron (BA.1) and blood samples were then obtained one and two weeks post-challenge. At the end of the follow-up period all animals were sacrificed, and all major organs were examined, with particular care paid to the pulmonary system. Tissue samples from all levels of the respiratory tract were collected and processed for histopathological examination. Slides were digitally scanned by an Aperio scanner and remotely viewed using the web-based HALO Link platform by a board-certified pathologist with specialized training in respiratory tract pathology in NHPs. Lung histopathology scores were blindly generated through the evaluation of all lung lobes from each animal and a grading system was used to determine severity.  

Upon booster administration, regardless of vaccine used, a rapid and robust increase in humoral immune responses occurred in animals that had been previously immunized with Ad26.COV2.S, as measured by both neutralizing and binding antibodies. They also found that all three vaccine booster approaches resulted in augmented cellular SARS-CoV-2-specific immune responses by measuring antigen-specific memory immunoglobulin G+ B cells and T-cell responses. Upon challenge with SARS-COV-2 Omicron BA.1, animals that had been boosted demonstrated decreased viral loads by nasal swab and bronchoalveolar lavage (BAL). Additionally, they found that boosting with the Ad26.COV2.S.529 or combination vaccine conferred a higher degree of protection to the lower respiratory tract against SARS-CoV-2 Omicron BA.1 compared to Ad26.COV2.S as evaluated by viral load and gross and histopathologic examination. A correlate of protection analysis was done and found that Omicron BA.1 neutralizing antibody titer levels and T-cell responses at week six were inversely correlated with total viral load in BAL, suggesting that antibody and T-cell responses may contribute to the efficacy of these vaccinations. 

This study confirmed the continued efficacy of the Wuhan-Hu-1 Spike based vaccine Ad26.COV2.S and demonstrated that booster immunization with vaccines targeted to VoC can provide moderate improvement in Omicron neutralizing antibody responses and protection from Omicron infection. This moderate improvement was especially evident in the lower respiratory tract. Boosting with the original Wuhan-Hu-1 Spike based vaccine continues to confer protection against severe COVID-19 disease, even in cases caused by VoC.