Declined antibody responses to COVID-19 mRNA vaccine within first three months

Background Although the SARS-CoV-2 mRNA vaccines have proven high efficacy, limited data exists on the duration of immune responses and their relation to age and side effects. Methods We studied the antibody and memory T cell responses to Spike protein after the two-dose Comirnaty mRNA vaccine in 122 volunteers up to 3 months and correlated the findings with age and side effects. Findings We found a robust antibody response after the second vaccination dose. However, the antibody levels declined at 6 and 12 weeks postvaccination, indicating a waning of the immune response. Regardless, the average levels remained higher compared to pre-vaccination or in COVID-19 convalescent individuals. The antibodies efficiently blocked ACE2 receptor binding to Spike protein of four variants of concern at one week but this was decreased at three months, in particular with B.1.351 and P1 isolates. 87% of individuals developed Spike-specific memory T cell responses, which were lower in individuals with increased proportions of immunosenescent CD8+ TEMRA cells. We found a decreased vaccination efficacy but fewer adverse events in older individuals, suggesting a detrimental impact of age on outcome. Interpretation The mRNA vaccine induces a strong antibody response to four variants at 1 week postvaccination but decreases thereafter, in particular among older individuals. T cell responses, although detectable in the majority, were lower in individuals with immunosenescence. The deterioration of vaccine response needs to be monitored to define the optimal time for the revaccination. Funding The Estonian Research Council, Icosagen Cell Factory, and SYNLAB Estonia. Evidence before this study The first studies addressing the immune responses in older individuals after the administration of SARS-CoV-2 mRNA vaccines have been published. We searched PubMed and medRxiv for publications on the immune response of SARS-CoV-2-mRNA vaccines, published in English, using the search terms “SARS-CoV-2”, “COVID-19”, “vaccine response”, “mRNA vaccine”, up to May 20th, 2021. To date, most mRNA vaccine response studies have not been peer-reviewed, and data on the dynamics of antibody response, role of age and side effects on SARS-CoV-2-mRNA vaccines in real vaccination situations is limited. Some studies have found a weaker immune response in older individuals after the first dose and these have been measured at a relatively short period (within one to two weeks) after the first dose but little longer-term evidence exists on the postvaccination antibody persistence. Added value of this study In this study, we assessed the antibody response up to three months after the full vaccination with Pfizer-BioNTech Comirnaty mRNA vaccine in 122 individuals. Our findings show strong Spike RBD antibody responses one week after the second dose with the capacity to block ACE2-Spike protein interaction, however, the antibodies declined significantly at three months after the second dose. The inhibition of ACE2-Spike interaction was weaker with South African (B.1.351) and Brazilian (P.1) than with Wuhan and UK (B.1.1.7) SARS-CoV-2 isolates. At three months 87% of vaccinated individuals developed either CD4+ or CD8+ T cell responses. Those negative for Spike-specific T cell response also tended to have lower Spike-specific antibody levels. In addition, CD4+ T cell response was decreased among vaccinated individuals with elevated levels of senescent CD8+ TEMRA cells. We found a weaker antibody response and faster waning of antibodies in older vaccinated individuals, which correlated with fewer side effects at the time of vaccinations. Implications of all the available evidence Our results show that two doses of Pfizer-BioNTech Comirnaty mRNA vaccine induce a strong antibody and T cell responses to Spike RBD region but the antibody levels are declined at three months after the second dose. Nevertheless, even at three months, the anti-Spike RBD antibody levels stay significantly higher than at prevaccination, after the first dose of vaccine, or in Covid-19 postinfection. Our findings implicate older individuals to have fewer vaccination adverse effects and weaker immune response after the vaccination and point to the need for more individualized vaccination protocols, in particular among older people. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The study was supported by the Centre of Excellence in Translational Genomics (EXCEGEN), and the Estonian Research Council grant PRG377, SYNLAB Estonia, and Icosagen Cell Factory. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study has been approved by the Research Ethics Committee of the University of Tartu on February 15, 2021 (nr 335/T-21). All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data is available on request