Factors contributing to a weak antibody response to the Pfizer COVID-19 vaccine

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the coronavirus disease 2019 (COVID-19), has infected over 241 million people worldwide and caused the deaths of over 4.9 million. As a result, efforts to contain the spread of this virus have included restrictions on movement outside the home, business and school closures, social distancing, and eventually, global vaccination campaigns.

A new study published on the preprint server medRxiv* discusses risk factors for the failure of seroconversion following full vaccination with one of the earliest vaccines to be rolled out. In this systematic review, the authors explain the impact of various factors on the antibody response to this vaccine.

Study: Effects of Age, Sex, Serostatus and Underlying Comorbidities on Humoral Response Post-SARS-CoV-2 Pfizer-BioNTech Vaccination – A Systematic Review. Image Credit: Flowersandtraveling / Shutterstock.com


The severe economic and social stress induced by the implementation of non-pharmaceutical interventions aimed at reducing transmission of SARS-CoV-2 culminated in the deployment of the first two vaccines against SARS-CoV-2 from Pfizer/BioNTech and Moderna. These two vaccines are based on a messenger ribonucleic acid (mRNA) platform, where the mRNA molecule encodes for the SARS-CoV-2 spike antigen within the host cell. The antigen is then expressed on the host cell surface, triggering the immune response by the host.

The resulting production of virus-specific antibodies is a key part of the protective immune response to the pathogen. Further, this response helps to prevent infection or dampen the inflammatory response to the infection, thus preventing disease progression.


The main factors that affect the humoral response to the vaccine include age, which reduces immunologic capability, especially among those with underlying medical conditions. This phenomenon, called immunosenescence, is linked with a poor response to vaccination in general, and with the influenza A H1/N1 vaccination in particular.

The resulting low levels of antibodies could lead to increased susceptibility to infection and a shorter period of vaccine-induced protection in older people.

Many studies have reported higher antibody titer values after vaccination compared to older individuals, corroborating the lower antibody response among this group. There are also differences in memory B-cells and plasma cells among those older than 65 years, which have been associated with the expansion of a subset of B-cells with a pro-inflammatory profile.

The reduced titers of vaccine spike-specific antibodies in the elderly increased the chances of poor or no response, as well as a more rapid decline in antibody levels. This difference was greatest after one dose, with the gap narrowing over time and especially after the booster dose.

In fact, the younger the age group, the higher the vaccine-induced antibody titer relative to those older. The largest gap has been observed in those with the greatest age differences.


Females showed higher antibody titer values, which, along with the innate response, is positively and negatively regulated by female and male hormones, respectively. Since sex hormone levels drop with age, the low estrogen levels after menopause cause a reduction in the strength of the immune response.

Childhood vaccination studies have shown that the presence of the extra X chromosome may play a role in immunity, including the immunomodulatory microRNAs (miRNAs). Correspondingly, adverse events and humoral responses are higher among women.

Females produce increased immunoglobulin G (IgG) at both 21 and 28 days after vaccination as compared to males after receiving the Pfizer vaccine. This confirms earlier findings that female genes are more resistant to viral infections, showing greater inflammatory, antiviral, and antibody signaling due to the X chromosomes and sex hormones.

Estrogen is already known to suppress SARS-CoV-2 replication, acting via enhanced metabolic function and genetic modifications to keep the cell healthy. Testosterone blocks immune function through its effects on androgen receptors and immune cells, thus reducing inflammation while increasing anti-inflammatory responses.

Serologic status

Earlier studies have shown that those with SARS-CoV-2 infection have prompt antibody responses, affecting the ultimate response to the vaccine. This is thought to be the result of intact memory B-cells from the prior infection.

Seropositive individuals had antibody titers that were multi-fold higher than those who lacked virus-specific antibodies at baseline in some studies, though others dispute this finding. Accordingly, some investigators recommend two vaccine doses and others only one to confer protection against the virus.

Sometimes, the differences in titer values could be due to the variation in viral load during mild or severe COVID-19. Other possible reasons include a high immune response, amplification of specific B-cell plasmablasts, or, with severe disease, high and prolonged levels of B-cell receptor stimulation.


Some conditions that are associated with an adverse outcome in COVID-19 patients include chronic kidney disease, diabetes mellitus, and cardiovascular disease. The link is thought to be the disordered metabolism that causes the impairment of immune cells.

The effect is exacerbated by increasing age over 60 years since this worsens the already reduced antibody response. Nonetheless, vaccination is the most cost-effective preventative measure, though dose adjustment may be required.

Patients on hemodialysis are especially prone to failure of seroconversion, though the response was better among those with a prior history of natural infection with the virus. Transplant patients were 90% more likely to have a poor immune response to the vaccine, with antibodies developing in only a few patients at a later stage and waning rapidly, never reaching a protective level. The reason for this observation is likely the immunosuppressive medications that these patients are prescribed.

In contrast, cancer patients showed a distinct lag that eventually resolved after the second dose. Patients with the autoimmune disease showed a tendency towards lower levels of humoral immunity, supporting the withdrawal of specific anti-inflammatory drugs such as rituximab and abatacept in combination with methotrexate until the vaccine has time to produce an immune response.

Unhealthy lifestyles and metabolic ill-health are also associated with poor immune responses to the vaccine. The higher the body mass index, the lower the antibody titer post-vaccination, and similarly with higher blood lipid levels. In fact, the anti-spike IgG levels were 70% greater in those with normal blood lipids.

This could be due to the release of adipokines that link cell metabolism to the immune response. This is particularly true for leptin, which regulates and coordinates energy metabolism in cells with the metabolic and immune responses. Hypertension is also reported to be linked to a reduced antibody production following vaccination against SARS-CoV-2.

Smoking also acts through nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) signaling pathways, as well as epigenetic mechanisms to impair humoral immunity by over 40%.


Prior infection with SARS-CoV-2 boosts the antibody response to the vaccine, while the presence of other medical illnesses and metabolic abnormalities is linked to impairment of the humoral arm of the adaptive immune response, either directly or through the use of immunosuppressive medications. In these groups, a third dose may not only boost antibody titers to protective levels but could also increase their immunity to variants of concern.

The difference in antibody titer values with age reflects the need for a second or third dose to ensure an adequate protective humoral response in older people. Secondly, it indicates the need to adapt vaccination programs in order to produce the most successful strategies that can adjust for reduced immune responses due to age.

The importance of monitoring humoral immunity seems almost unquestionable for prioritizing vaccine boosters, including new vaccines able to efficiently protect against current and potentially future SARS-CoV-2 drifted VoC. Their administration could provide the best compromise between the still limited availability and the highest clinical efficacy in averting or limiting COVID-19 infections and/or severe illness in especially vulnerable populations.”

*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:
Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.


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