Recombinant adjuvanted zoster vaccination with lower risk of COVID-19 diagnosis and hospitalization

An international team of scientists has observed that the immunity induced by recombinant adjuvanted zoster vaccine (RZV) offers heterologous protection, reducing the risk of coronavirus disease 2019 (COVID-19) diagnosis and hospitalization.

Study: Recombinant adjuvanted zoster vaccine and reduced risk of COVID-19 diagnosis and hospitalization in elderly adults.  Image credit: Halfpoint / ShutterstockExamination: Recombinant adjuvanted zoster vaccine and reduced risk of COVID-19 diagnosis and hospitalization in elderly adults. Image credit: Halfpoint / Shutterstock

The study, recently published in Journal of Infectious Diseases, extended over the first year of the COVID-19 pandemic prior to the availability of the COVID-19 vaccine, providing evidence of a reduced burden of COVID-19 in RZV recipients over 50 years of age.


By December 2021, only 58.1% of the global population is fully vaccinated according to the World Health Organization (WHO) COVID-19 Dashboard. The ongoing fight against the etiological remedy, severe acute respiratory syndrome 2 (SARS-CoV-2), continues in the light of new variants with renewed policies and mitigating efforts.

Although the variants infect populations that have acquired a SARS-CoV-2-specific immunity through natural infections or vaccinations, many studies have examined heterologous protection provided by the innate immune system.

The heterologous protection provided by the immune system can extend the protective results of vaccinations and natural resistance to non-specific infections, sometimes for extended periods. Previous studies have shown that Bacillus Calmette-Guerin (BCG), measles, oral polio and influenza vaccines induced the immune system to protect against heterologous infections.

Based on this, the researchers in this study assumed that the recombinant adjuvanted zoster vaccine (RZV) containing AS01 adjuvant could induce trained immunity to SARS-CoV-2 among individuals, especially the older adults.

RZV is administered to prevent shingles – a painful rash on the face, upper body or body of adults 50 years of age and older. The AS01 adjuvant in RZV elicits an innate immune response and robust cellular and humoral responses.

Therefore, the researchers in this study assessed the association between RZV vaccines and COVID-19 results.

Study design and results

The researchers conducted an observational study at Kaiser Permanente Southern California (KPSC), an integrated health care system. The study cohort included one set of individuals over the age of 50 who had either 1 dose of RZV (n = 149,244) or 2 doses of RZV (n = 94,895) and another set of RZV unvaccinated individuals (n = 298,488). The recipients of the ≥1 RZV dose were matched 1: 2 with the RZV unvaccinated subjects.

The researchers looked for the following results: 1) COVID-19 diagnosis, positive SARS-CoV-2 molecular test or COVID-19 diagnosis code and 2) COVID-19 hospitalization, SARS-CoV-2 positive test in or ≤7 days before admission, or a COVID-19 diagnostic code during hospitalization. In the study, the researchers used the Kaplan-Meier method and Cox proportional hazards regression.

The researchers observed that 1-dose and 2-dose RZV recipients had a 16% and 19% lower frequency of COVID-19 diagnosis and a 32% and 36% lower frequency of COVID-19 hospitalization, respectively, compared to the RZV -unvaccinated persons. By analyzing the sensitivity of the study, the researchers observed similar results among individuals who received the flu vaccine but no other vaccine. Among these, RZV recipients have a lower frequency of COVID-19 diagnosis and hospitalization. This suggests that “influenza vaccination or the healthy vaccinated bias had a minimal impact on the observations.”

In addition, the researchers also performed a test-negative design to test the RZV recipients in positive test results (those who tested positive for SARS-CoV-2, n = 75,726) and in negative controls (n = 340,898). The researchers noted that the cases showed significantly less morbidity, which supported the results observed in the study.

Although the mechanism of heterologous immunity is still unclear, the researchers described that exposure to such stimuli (RZV vaccine in this case) induced epigenetic and functional changes in the immune cells, generating trained innate immunity. This is associated with cytokine responses – which lead to reactivity to heterologous infections, including SARS-C0V-2 infections.

The early trigger of the immune response also poses a challenge to viral replication, inhibiting the virus early in the infection and thus possibly reducing the risk of serious disease. The researchers noted that this protection against congenital immunity controls coronavirus infection in animal reservoirs.

Interestingly, the researchers observed that this may be the reason why children have reduced the severity of COVID-19 disease compared to adults. The adjuvant used in the vaccine may also activate the immune responses, leading to a reduced risk of COVID-19.


This study was performed in the first year of the COVID-19 pandemic before the vaccines became available. The researchers adjusted their analysis for potential confounders, including other vaccinations, and found that the risk of COVID-19 diagnosis and hospitalization was reduced among RZV recipients compared to unvaccinated individuals.

The study suggests that RZV may elicit lasting innate immune responses in the elderly, providing heterologous protection against COVID-19. The researchers call for further study of vaccine-induced trained innate immunity to potential future infections.


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