Pillar 4
Functional Genomics & Structure-Function of VOCs

Neutralizing antibodies are generated in response to vaccination and infection and their function is to block entry of a pathogen into host cells. The Omicron variants of SARS-CoV-2 contain mutations in the spike protein sequence that can escape recognition by neutralizing antibodies, which can allow the SARS-CoV-2 viral variant to evade immunity. It has been suggested that viral evolution in immunocompromised patients may be important in the emergence of variants where viral replication is permitted, however the extent of immune escape in immunocompromised transplant patients remains poorly understood. In early 2022, the BA.1 subvariant was dominant, and new strains including BA.4/5 were emerging. Spike sequences of BA.4/5 subvariant are similar to BA.1 and BA.2, but differences in disease severity and molecular presentation were perhaps owing to sequences outside of spike.

The main objective of this research was to determine if vaccinated, BA.1-infected and recovered solid organ transplant recipients could mount a cross-neutralization response against BA.4/5 variant.  Uninfected transplant recipients with 3 doses of mRNA-1273 (Moderna), and uninfected healthcare workers with 3 doses of BNT-162b2 (Pfizer) were used for comparison.  The study measured neutralizing antibody levels in serum using a pseudotyped viral-like particle assay.  Neutralizing antibody responses against BA.1 were measured in 88% of BA.1 recovered transplant recipients.  Neutralizing antibody responses against BA.4/5 were seen in 69.3% of transplant recipients who had experienced BA.1 infection, and levels of neutralizing antibodies against BA.4/5 in the infected/recovered group were similar to those of vaccinated healthcare workers.  Neutralization of BA.4/5 was ~17 fold lower than BA.1 in infected transplant recipients. Triple-vaccinated transplant recipients had lower neutralizing antibodies against BA.4/5 compared to those with hybrid immunity or vaccinated healthcare workers. By 6 months post infection, levels of BA.4/5 neutralizing antibody fell by approximately 3-fold for approximately half of the patients.  The research team also looked at T cell responses after stimulation with BA.1 spike peptides and saw that those who were also negative for BA.4/5 neutralizing antibodies had similar levels of functional T cells to those who were positive for BA.4/5 neutralization which suggests that T cell activity may be conserved across BA.1 and BA.4/5 variants.

Overall, this study demonstrates that transplant recipients who recovered from BA.1 infection develop BA.4/5 cross-neutralizing responses, but at a lower frequency and lower level, with levels that wane over time. In addition, triple-mRNA vaccination on its own (in the uninfected transplant recipient cohort) induced minimal BA.4/5 neutralization. In this study, the additive effect of natural infection plus immunization resulted in higher cross-protective immunity compared with vaccination alone. Infection, however, is to be avoided because of the potential for severe disease, long COVID, and public health implications. Therefore, a solution may be updating variant-specific vaccine boosters, whereas waning that was observed may have implications for the timing of booster vaccines after infection.

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Impact of Omicron BA.1 infection on BA.4/5 immunity in transplant recipients. Victor H. Ferreira, Queenie Hu, Alexandra Kurtesi, Javier T. Solera, Matthew Ierullo, Anne-Claude Gingras, Deepali Kumar, Atul Humar. American Journal of Transplantation. 2023.02.23.27251-7; https://www.amjtransplant.org/article/S1600-6135(22)27251-7/fulltext