Tiny viruses are always trying to find paths into the body so they can invade cells and produce more viruses. When the viruses are successful, we get sick. Luckily, our immune systems have evolved to remember which viruses have made us sick in the past, so when the same invaders try again, they are quickly eliminated and cannot cause illness. While protective in the short term, natural immunity for any particular virus can fade over time. Getting sick to acquire natural immunity is risky. It can lead to a virus spreading to others, putting immunocompromised people at risk and, in some cases, putting extra strain on healthcare resources. Vaccines overcome these challenges by training our immune systems to recognize invaders and attack them before we get sick. The degree of protection offered by vaccines can depend on whether individuals have had a prior infection with a particular virus.
During the COVID-19 pandemic, scientists worked tirelessly to develop vaccines and clinical trials to evaluate their efficacy. Thousands of people volunteered for these clinical trials, and, eventually, vaccines against the SARS-CoV-2 virus were widely available. If you’re reading this article, chances are you have received several doses of these vaccines. Clearly, this is a massive success story, and the coordinated efforts of the researchers administering the vaccine trials have left behind mountains of data that will help inform vaccine regimens, clinical trial designs, and pandemic preparedness in the future. Now, researchers like Dr. Aaron Hudson and his colleagues are digging through some of that data to glean new insights into vaccine efficacy six years later. “People have compared efficacy of different COVID vaccines, but there are other important factors, too. In my paper…I was looking at how well these different COVID vaccines were able to induce immune responses in study participants,” explains Hudson.
Scientists designed COVID vaccine clinical trials to collect similar data at similar timepoints. Because of these “harmonized protocols,” the team was able to analyze data from six different phase 3 clinical trials. They compared COVID neutralizing antibody (nAb) concentrations in the serum of people who had a prior COVID infection and a vaccine dose (hybrid immunity), people who had two vaccine doses (vaccine immunity), or people with only a prior infection (natural immunity). nAbs prevent COVID from entering cells, and levels of nAbs correlate with protection from infection. They found that participants with hybrid immunity had the highest levels of nAbs across all trials. Those with vaccine immunity had lower levels of nAbs, and response rates varied a lot depending on which vaccine the participants received. Unsurprisingly, participants with only natural immunity had the lowest levels of nAbs across trials.
Next, the team analyzed how nAb levels changed after individual vaccine doses. In participants with vaccine immunity, they observed a bigger increase in nAb levels after the second dose than after the first dose. For participants with hybrid immunity, there was a large increase in nAb levels after the first dose. Together, these results suggest that two vaccine doses are crucial to fully protect individuals who have not had prior infection, while those who have had a prior infection are protected after one vaccine dose.
Scientists estimate that more than 87% of people in the US had COVID by the end of 2023. Currently, a single dose of the COVID vaccine is recommended regardless of vaccination or infection history. The data in this study and others bolster these recommendations by showing that prior infections combined with one vaccine dose offer superior immunity. In the future, these recommendations will undoubtedly begin to shift as new strains of COVID emerge or as new studies interrogate other nuances of the pandemic.
This work was supported by funding from the National Institutes of Health, US Department of Health and Human Services, Administration for Strategic Preparedness and Response, and the Biomedical Advanced Research and Development Authority.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Members Drs. Aaron Hudson, Holly Janes, James Kublin, Larry Corey, and Peter Gilbert contributed to this work.
Hudson A, Borgetti S, Rick AM, Laurens MB, Robinson ST, Gay CL, Baden LR, Goepfert PA, Rouphael N, El Sahly HM, Gray GE, Grinsztejn B, Sobieszczyk ME, Falsey AR, Huang Y, Janes H, Follman D, Koup RA, Priddy F, Hendriks J, Shoemaker K, Dunkle LM, de Bruyn G, Devlin L, Neuzil KM, Kublin JG, Corey L, Walsh SR, Kotloff KL, Gilbert PB. 2026. Impact of prior SARS-CoV-2 acquisition on binding and neutralizing antibody responses following COVID-19 vaccination: A cross-protocol analysis of individual-level data from six phase 3 clinical trials. Vaccine. 2026 Apr 2:77:128380. https://doi.org/10.1016/j.vaccine.2026.128380.
Kelsey Woodruff is a PhD candidate in the Termini Lab at Fred Hutch Cancer Center. She studies how acute myeloid leukemia cells remodel the sugars on their membranes to reprogram cancer cell signaling. Originally from Indiana, she holds a bachelor's degree in Biochemistry from Ball State University. Outside of lab, you can find her crocheting and enjoying the Seattle summers.
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