An international team of scientists has observed that the immunity elicited by recombinant adjuvanted zoster vaccine (RZV) offers heterologous protection, reducing the risk of coronavirus disease 2019 (COVID-19) diagnosis and hospitalization.
The study, recently published in The Journal of Infectious Diseases, spanned the first year of the COVID-19 pandemic prior to the COVID-19 vaccine availability, providing evidence of a reduced burden of COVID-19 in RZV recipients who were over 50 years old.
As of December 2021, only 58.1% of the global population is fully vaccinated, according to the World Health Organisation (WHO) COVID-19 Dashboard. The ongoing fight against the etiological agent, severe acute respiratory syndrome 2 (SARS-CoV-2), is continuing in the face of emerging variants with renewed policies and mitigating efforts.
Although the variants are infecting populations that have acquired a SARS-CoV-2-specific immunity through natural infections or vaccinations, many studies investigated heterologous protection provided by the innate immune system.
The heterologous protection conferred by the immune system can broaden the protective outcomes of vaccinations and natural resistance to non-specific infections, sometimes for prolonged periods. Previous studies have demonstrated 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 the present study hypothesized that the recombinant adjuvanted zoster vaccine (RZV) containing AS01 adjuvant could induce trained immunity against SARS-CoV-2 among individuals, especially the older adults.
RZV is administered to prevent shingles - a painful rash on the face, torso, or body, in adults who are 50 years and older. The AS01 adjuvant in RZV elicits an innate immune response and robust cellular and humoral responses.
Therefore, in the present study, the researchers evaluated the association of RZV vaccines with COVID-19 outcomes.
Study design and findings
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 ages over 50 years, 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 ≥1 RZV dose were matched 1:2 with the RZV unvaccinated individuals.
The researchers looked for the following outcomes: 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 during or ≤7 days before hospitalization, or a COVID-19 diagnosis code during hospitalization. In the study, the researchers used the Kaplan-Meier method and the Cox proportional hazards regression.
The researchers observed that 1-dose and 2-doses RZV recipients had a 16% and 19% lower rate of COVID-19 diagnosis and a 32% and 36% lower rate of COVID-19 hospitalization respectively, compared to the RZV unvaccinated individuals. Analyzing the sensitivity of the study, the researchers observed similar results among individuals who received the influenza vaccine but no other vaccine. Among these, the RZV recipients have a lower rate of COVID-19 diagnosis and hospitalization. This is suggestive that ‘the influenza vaccination or healthy vaccinee bias had a minimal impact on the observations.'
Further, the researchers also conducted a test-negative design to test the RZV recipients in positive-test outcomes (those who tested positive for SARS-CoV-2, n=75,726) and in negative controls (n=340,898). The researchers noted that the cases significantly presented less morbidity, supporting the results observed in the study.
Although the mechanism of heterologous immunity is yet 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 linked to cytokine responses - that lead to reactiveness to heterologous infections, including SARS-C0V-2 infections.
The early trigger of the immune response also poses a challenge to the viral replication, inhibiting the virus early in the infection, and thus, possibly reducing the risk of severe disease. The researchers noted that this protection from innate immunity controls the 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. Also, the adjuvant used in the vaccine may activate the immune responses leading to a reduced risk of COVID-19.
This study was conducted in the first year of the COVID-19 pandemic before the vaccines were 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 durable innate immune responses in the elderly conferring heterologous protection against COVID-19. The researchers call for further study of vaccine-elicited trained innate immunity against potential future infections.