In our post-COVID pandemic world, several lingering questions remain pertaining to the culprit, SARS-CoV-2. While we can’t answer the question of, will another SARS-CoV-2 pandemic happen again? We can ensure our offensive game is stronger by striving to answer questions like, how good are the SARS-CoV-2 vaccines? And importantly, how effective are they against virus variants that escape detection by a vaccinated individual’s “trained” immune system? A team of researchers led by Fred Hutchinson Cancer Center investigators Mr. Craig Magaret, the Director of the Fred Hutchinson HIV Vaccine Trials Network Bioinformatics Core, and Dr. Peter Gilbert, a Professor in the Vaccine and Infectious Disease and Public Health Sciences Divisions, sought to investigate these questions and published their findings in Nature Communications. Vaccine trial data including SARS-CoV-2 sequences and patient disease severity outcomes during infection helped to answer these questions. Unsurprisingly, the vaccine efficacy was best for variants closely related to the reference isolate—what the vaccine was engineered to target. However, even a less effective vaccine could still protect against severe-critical COVID-19 for most variant lineages. These findings and the recently characterized Lambda lineage escape mutants, which contribute lingering mutations in current circulating strains, will guide vaccination recommendations and next-generation vaccine formulations as an impenetrable offensive plan.
The Janssen Ad26.COV2.S vaccine, a single-dose DNA-based adenovirus vaccine, was distributed globally during the COVID-19 pandemic. The researchers wanted to know how changes in the genetic code of the SARS-CoV-2 virus—specifically the Spike protein used as the antigen of choice to elicit an immune response—affected the efficacy of vaccination to prevent moderate and severe-critical disease. To do this, the researchers used data from the Coronavirus Prevention Network (CoVPN) 3003 ENSEMBLE efficacy trial of the Janssen Ad26.COV2.S single-dose COVID-19 vaccine vs placebo. “The trial took place in the United States, South Africa, and six countries in Latin America,” shared Mr. Magaret. “Because the Latin American countries constituted the largest cohort of these three regions and exhibited the greatest viral diversity, our analysis focuses on this region.” This study was comprised of more than 40,000 trial participants which included cohorts from Latin American countries totaling 300 vaccine recipients and just over 600 placebo-group individuals with COVID-19 and sequence data. In these countries, the circulating SARS-CoV-2 variants at the time of the trial included Alpha, Gamma, Zeta, Lambda, and Mu. These variant lineages were named in succession from Alpha to Mu and exhibited increased sequence variation over time from the reference isolate which preceded the Alpha variant. Importantly, the reference sequence Spike protein published on July 18th, 2020 was the target antigen used in the Janssen Ad26.COV2.S vaccine formulation.
“Our key finding is that the more dissimilar an infecting virus is from the vaccine, the less able the vaccine is to protect against it,” commented Mr. Magaret. “This finding means that viral similarity to the vaccine can be regarded as a biomarker of vaccine efficacy, which can have several public health applications, including guiding the selection of which strains to use with next-generation vaccines, and modeling the efficacy of a vaccine against circulating viral strains.” Similar to other studies, the researchers highlighted the Lambda lineage as a vaccine escape variant with only about 11% vaccine efficacy. “Lambda appears to be especially well-adapted to evading vaccine-induced immune pressure,” stated Mr. Magaret. “While Lambda succumbed to the superior fitness of Delta and Omicron and eventually sank without a trace, many of Lambda's signature mutations have resurfaced in recent dominant lineages.” Many of these were also noted in the researcher’s antibody escape evaluation of mutated Spike amino acid residues in which human antibodies specific to the reference SARS-CoV-2 Spike protein did not bind to the mutant Spike proteins. “Of special note is the F490S mutation: the vaccine worked best against the vaccine-insert F490 virus, and efficacy suffered if the phenylalanine (F) was substituted with a serine (S),” stated Mr. Magaret. “While rare until the end of 2022, this F490S mutation became dominant in early 2023 with the emergence of the XBB.1.5 recombinant lineage.”
To tease out how the viral genetics and vaccine efficacy impacted the outcome of severe-critical COVID, the researchers performed several types of comparative analyses. Mr. Magaret shared, “We found some trends with lower vaccine efficacy against viruses more dissimilar to the insert, especially in the Spike protein's N-terminal domain, but the results didn't pass our most-stringent criterion for statistical significance.” The key takeaway is that “the virus's genetic adaptations to evade the vaccine were not sufficient to ruin the efficacy of the vaccine to block severe COVID.”
This work contributes to our understanding of vaccine efficacy over time and in the presence of variant lineages and will guide strategic design of future SARS-CoV-2 vaccines that include added protection from viruses with escape mutations (e.g. serine at 490 in the spike protein). Furthermore, continued sequencing of circulating SARS-CoV-2 variants can be used as biomarkers of vaccine efficacy to help optimize vaccine reformulations. These studies required expertise and resources from an extensive group of collaborating researchers. “We'd like to especially provide our thanks to Alex Greninger and Pavitra Roychoudhury of the UW Virology sequencing lab, who generated the sequences for this and many other CoVPN studies,” commented Dr. Gilbert. “The sequencing data were core to this analysis, and the quality of the data was top tier.”
The spotlighted research was funded by Janssen/ Johnson & Johnson, National Institutes of Health, Henry M. Jackson Foundation, U.S. Department of the Army, Pew Biomedical, Burroughs Wellcome fund, and Howard Hughes Medical Institute.
Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members Dr. Larry Corey, Dr. Ollivier Hyrien, and Dr. Peter Gilbert contributed to this work.
Magaret CA, Li L, deCamp AC, Rolland M, Juraska M, Williamson BD, Ludwig J, Molitor C, Benkeser D, Luedtke A, Simpkins B, Heng F, Sun Y, Carpp LN, Bai H, Dearlove BL, Giorgi EE, Jongeneelen M, Brandenburg B, McCallum M, Bowen JE, Veesler D, Sadoff J, Gray GE, Roels S, Vandebosch A, Stieh DJ, Le Gars M, Vingerhoets J, Grinsztejn B, Goepfert PA, de Sousa LP, Silva MST, Casapia M, Losso MH, Little SJ, Gaur A, Bekker LG, Garrett N, Truyers C, Van Dromme I, Swann E, Marovich MA, Follmann D, Neuzil KM, Corey L, Greninger AL, Roychoudhury P, Hyrien O, Gilbert PB. 2024. Quantifying how single dose Ad26.COV2.S vaccine efficacy depends on Spike sequence features. Nat Commun. 15(1):2175.
