A recent study has provided the first side-by-side comparison of how three major COVID-19 vaccine types differ in triggering immune responses and sustaining protection, according to an analysis published in JCI Insight.
While three vaccine subtypes (adenovirus-based, mRNA, and protein-based) were widely deployed during the pandemic, investigators say their immunological profiles and optimal use cases are more nuanced than previously understood.
“During the COVID-19 pandemic, three main types of vaccines were used around the world: Adenovirus-based vaccines like the AstraZeneca, ChAdOx1, and Johnson & Johnson shots, mRNA vaccines like Pfizer and Moderna, and protein vaccines like Novavax,” said Pablo Penaloza-MacMaster, PhD, adjunct associate professor of Microbiology-Immunology, who was senior author of the study. “All of them worked, but we didn’t have a clear and rigorous side-by-side comparison of how they differ in the way they trigger the immune system… This study was designed to fill that gap.”
The study, conducted in mice, revealed that adenovirus-based (Ad5) vaccines induced the most sustained antigen expression lasting more than a week and produced stronger immune responses after a single dose. In contrast, mRNA vaccines elicited robust immune responses but only after two doses, and triggered early immune activation within just a few hours, which could explain transient side effects. Protein-based vaccines were the weakest overall, particularly for T-cell responses, but caused less inflammation, potentially making them more tolerable for individuals sensitive to vaccine reactions.
“The key takeaway is that different vaccine platforms work best under different conditions, so there isn’t a single ‘winner,’” Penaloza-MacMaster said. “The context matters. Adenovirus vaccines may be great in situations where you want more sustained antigen expression and for cheap and quick, one-shot protection, but only in people without preexisting immunity to the vector. However, mRNA vaccines could be better for booster strategies and in people who might already have been exposed to adenoviruses.”
Looking ahead, Penaloza-MacMaster and his team plan to apply these insights to other diseases.
“The next step is to take what we’ve learned from this comparative study and apply it to challenging diseases, especially HIV, which has remained one of the hardest viruses to vaccinate against,” Penaloza-MacMaster said. “By understanding how different vaccine platforms like adenoviral vectors, mRNA, and protein interact with the immune system, we hope to identify combinations that generate more durable and protective immunity. For example, we have found that priming with adenovirus and boosting with protein (heterologous vaccine regimen) is particularly effective for antibody responses. However, the other way around is not as effective, so when it comes to vaccines, A+B is not always the same as B+A.”
The findings underscore the importance of tailoring vaccine strategies to individual and population-level immunity — a lesson that could shape the development of next-generation vaccines for COVID-19 and beyond, he said.
The study was supported by Northwestern University and Beth Israel Deaconess Medical Center.
