Long-term humoral response and its determinants following 2- and 3-dose COVID-19 mRNA vaccines

Long-term humoral response and its determinants following 2- and 3-dose COVID-19 mRNA vaccines

In a recent study posted to the medRxiv* preprint server, researchers compared the waning of vaccine-induced immunity from two and three doses of messenger ribonucleic acid (mRNA) coronavirus disease 2019 (COVID-19) Pfizer-BioNTech vaccine BNT162b2 by conducting a repeated serological study to assess the prolonged humoral response.

Study: Durability and determinants of anti-SARS-CoV-2 spike antibodies following the second and third doses of mRNA COVID-19 vaccine. Image Credit: Christoph Burgstedt/Shutterstock


The concerted global efforts to develop vaccines and administer a primary two-dose vaccination regimen to large portions of the population worldwide have resulted in limiting the morbidity and mortality associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections.

Various studies have assessed the long-term efficacy and waning of the primary two doses in different age groups consisting of the elderly population, females, and people with previous SARS-CoV-2 infections. The findings from these studies have been instrumental in formulating public health policies regarding booster vaccinations.

However, the waning of antibody responses based on comorbidities such as obesity, immunosuppression, and other serious diseases has not been evaluated for the primary vaccination regimen or the third booster dose. Understanding the factors determining long-term humoral immunity is critical for formulating public health decisions during the continuing COVID-19 pandemic.

About the study

In the present study, the researchers conducted six serological surveys among staff at the National Center for Global Health and Medicine (NCGM) in Japan between July 2020 and June 2022. At NCGM, the in-house vaccination provided to the staff comprises two doses of the Pfizer-BioNTech BNT162b2 mRNA vaccine between March and June 2021 and a booster dose between December 2021 and February 2022.

During the survey, the antibodies against the SARS-CoV-2 nucleocapsid and spike proteins were measured, and patient information comprising data on COVID-19 vaccination status, previous SARS-CoV-2 infections, comorbidities, body composition, and behavioral factors were collected. The vaccination status and self-reported previous SARS-CoV-2 infections were confirmed using the records at NCGM.

From the gathered data, some were excluded due to missing information on body mass index, immunosuppressive treatments, underlying health conditions, smoking or alcohol drinking behavior, and mismatch between SARS-CoV-2 infection reports and seropositive anti-SARS-CoV-2 nucleocapsid protein assays.

Information on demographic factors, body mass index, disease, immunosuppressive therapy history, and tobacco and alcohol use were gathered from a questionnaire survey after informed consent was obtained. The co-existing diseases included in the questionnaire comprised cardiovascular diseases, kidney diseases, hypertension, cancer, dyslipidemia, and diabetes. The survey also requested information on anti-cancer treatment, non-topical and non-inhaled steroids, and immunosuppressants. Consumption of alcohol once a week was considered regular alcohol use.

Statistical analyses were performed to find correlations between waning antibody titers and demographic, comorbidity, and lifestyle-related determinants.


The results reported an overall decrease in antibody waning rates after the booster vaccine dose. Additionally, the antibody waning rates in individuals with hybrid immunity from vaccination and previous SARS-CoV-2 infections were further decreased. Individuals with three vaccine doses and a previous SARS-CoV-2 infection exhibited a 21% antibody waning per 30 days compared to individuals with two vaccine doses and a previous SARS-CoV-2 infection, who had a waning rate of 16% every 30 days.

Determinant variables such as progressing age, obesity, comorbid diseases, smoking, alcohol consumption, immunosuppressive therapy, and the male sex were associated with decreasing antibody titers after the second dose. These correlations disappeared for antibody titers after the booster dose, except in the case of immunosuppressive therapy and the female sex.

While the results suggested that hybrid immunity resulted in a lower antibody waning rate than vaccination-induced immunity alone, an interesting pattern was observed where two doses and previous SARS-CoV-2 infections resulted in more durable antibodies than three doses and previous infection. This suggested that SARS-CoV-2 infections produced more durable antibodies than vaccinations.

Furthermore, there were no differences in antibody titer durability based on the sequence of infections and vaccinations, or the dominant variant in circulation during infection, suggesting that the longevity of antibody titers was not influenced by the variant responsible for the SARS-CoV-2 infection.

The waning of antibody titers in individuals undergoing immunosuppressive therapy, regardless of the number of vaccine doses, indicated the need for constant infection monitoring and increased booster vaccinations for these individuals.


Overall, the results indicated that antibody titers were more durable and long-lived in individuals who received booster vaccinations and had previous SARS-CoV-2 infections, irrespective of the infective variant.

Furthermore, while primary vaccinations were associated with waning antibody titers in the elderly, comorbid, obese, male, or immunosuppressive therapy receiving groups, these associations were not apparent after the third vaccination dose, except for females and individuals under immunosuppressive therapy. The results highlight the need to monitor infections and administer booster doses to patients undergoing immunosuppressive therapy.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
  • Yamamoto, S. et al. (2022) "Durability and determinants of anti-SARS-CoV-2 spike antibodies following the second and third doses of mRNA COVID-19 vaccine". medRxiv. doi: 10.1101/2022.11.07.22282054. https://www.medrxiv.org/content/10.1101/2022.11.07.22282054v1

Posted in: Medical Science News | Medical Research News | Disease/Infection News

Tags: Alcohol, Antibodies, Antibody, Body Mass Index, Cancer, Cancer Treatment, Coronavirus, Coronavirus Disease COVID-19, covid-19, Diabetes, Dyslipidemia, Efficacy, Global Health, immunity, Immunosuppression, Kidney, Medicine, Mortality, Obesity, Pandemic, Protein, Public Health, Respiratory, Ribonucleic Acid, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Smoking, Syndrome, Tobacco, Vaccine

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Dr. Chinta Sidharthan

Chinta Sidharthan is a writer based in Bangalore, India. Her academic background is in evolutionary biology and genetics, and she has extensive experience in scientific research, teaching, science writing, and herpetology. Chinta holds a Ph.D. in evolutionary biology from the Indian Institute of Science and is passionate about science education, writing, animals, wildlife, and conservation. For her doctoral research, she explored the origins and diversification of blindsnakes in India, as a part of which she did extensive fieldwork in the jungles of southern India. She has received the Canadian Governor General’s bronze medal and Bangalore University gold medal for academic excellence and published her research in high-impact journals.

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