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What Are the Factors That Improve COVID Vaccine Antibody Response?

  • Authors: News Author: Miriam E. Tucker; CME Author: Charles P. Vega, MD
  • CME / ABIM MOC / CE Released: 4/2/2021
  • Valid for credit through: 4/2/2022, 11:59 PM EST
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Target Audience and Goal Statement

This activity is intended for all clinicians who advise patients about the COVID-19 vaccines.

The goal of this activity is to distinguish variables that might affect the immune response to COVID-19 vaccines.

Upon completion of this activity, participants will:

  • Analyze the relative efficacy of the currently available messenger RNA (mRNA) vaccines against COVID-19 after just one dose
  • Distinguish variables associated with a lower immune response following the mRNA COVID-19 vaccines
  • Outline implications for the healthcare team


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News Author

  • Miriam E. Tucker

    Freelance writer, Medscape


    Disclosure: Miriam E. Tucker has disclosed no relevant financial relationships.

CME Author

  • Charles P. Vega, MD

    Health Sciences Clinical Professor of Family Medicine
    University of California, Irvine School of Medicine
    Irvine, California


    Disclosure: Charles P. Vega, MD, has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for: GlaxoSmithKline

Editor/CME Reviewer

  • Esther Nyarko, PharmD

    Associate Director, Accreditation and Compliance Medscape, LLC


    Disclosure: Esther Nyarko, PharmD, has disclosed no relevant financial relationships.

Nurse Planner

  • Hazel Dennison, DNP, RN, FNP-BC, CHCP, CPHQ, CNE

    Associate Director, Accreditation and Compliance Medscape, LLC


    Disclosure: Hazel Dennison, DNP, RN, FNP-BC, CHCP, CPHQ, CNE, has disclosed no relevant financial relationships.

Medscape, LLC staff have disclosed that they have no relevant financial relationships.

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What Are the Factors That Improve COVID Vaccine Antibody Response?

Authors: News Author: Miriam E. Tucker; CME Author: Charles P. Vega, MDFaculty and Disclosures

CME / ABIM MOC / CE Released: 4/2/2021

Valid for credit through: 4/2/2022, 11:59 PM EST


Note: The information on the coronavirus outbreak is continually evolving. The content within this activity serves as a historical reference to the information that was available at the time of this publication. We continue to add to the collection of activities on this subject as new information becomes available. It is the policy of Medscape Education to avoid the mention of brand names or specific manufacturers in accredited educational activities. However, manufacturer names related to COVID-19 vaccines may be provided in this activity to promote clarity. The use of manufacturer names should not be viewed as an endorsement by Medscape of any specific product or manufacturer.

Clinical Context

One of the most important and controversial issues in the fight against the COVID-19 pandemic is the temporary application of just 1 dose of the currently available messenger RNA (mRNA)-based vaccines in the United States instead of the currently authorized 2-dose regimen. Proponents of a single-dose strategy argue that these vaccines still are effective against COVID-19 when applied as a single dose, and the current crisis in the United States coupled with problems with vaccine distribution and application mandates a single-dose approach to get as many people vaccinated as soon as possible.

These supporters of a single dose have some good points. First, it is very likely that single dosing will result in more people being vaccinated. In addition, the emergency use authorizations for both the Pfizer-BioNTech[1] and Moderna[2] vaccines cited good vaccine efficacy in a single dose (82% and 80.2%, respectively); however, there are real risks associated with significant delay of a booster dose of these vaccines. Would the protected period against COVID-19 be shortened without a booster? In addition, could the booster provide the additional support necessary as new variants off SARS-CoV-2 emerge? Finally, it is possible that a less effective vaccine might help select for variants that are more vaccine-resistant and possibly more virulent overall.

This debate will continue, fueled by the epidemiology of COVID-19 and the logistical challenge of vaccinating hundreds of millions of people, but what about clinical variables that might affect vaccine efficacy? The current study addresses this issue.

Study Synopsis and Perspective

The capacity to mount humoral immune responses to COVID-19 vaccinations may be reduced among people who are heavier, older, and male, new findings suggest.

The data pertain specifically to the mRNA vaccine, BNT162b2, developed by Pfizer Inc. and BioNTech SE. The study was conducted by Italian researchers and was published February 26 as a preprint.[3]

The study involved 248 healthcare workers who each received 2 doses of the vaccine. Of the participants, 99.5% developed a humoral immune response after the second dose. Those responses varied by body mass index (BMI), age, and sex.

"The findings imply that female, lean and young people have an increased capacity to mount humoral immune responses compared to male, overweight and older populations," said Raul Pellini, professor at the IRCCS Regina Elena National Cancer Institute, Rome, Italy, and colleagues.

"To our knowledge, this study is the first to analyze Covid-19 vaccine response in correlation to BMI," they noted.

"Although further studies are needed, this data may have important implications to the development of vaccination strategies for COVID-19, particularly in obese people," they wrote.

If the data are confirmed by larger studies, "giving obese people an extra dose of the vaccine or a higher dose could be options to be evaluated in this population."

Results Contrast With Pfizer Trials of Vaccine

The BMI finding seemingly contrasts with final data from the phase 3 clinical trial of the vaccine, which were reported in a supplement index to an article published December 31, 2020, in the New England Journal of Medicine.[4] In that study, vaccine efficacy did not differ by obesity status.

Asked to comment, Akiko Iwasaki, PhD, professor of immunology at the Howard Hughes Medical Institute and an investigator at Yale University School of Medicine, New Haven, Connecticut, noted that although the current Italian study showed somewhat lower levels of antibodies in people with obesity compared with people who did not have obesity, the phase 3 trial found no difference in symptomatic infection rates.

"These results indicate that even with a slightly lower level of antibody induced in obese people, that level was sufficient to protect against symptomatic infection," Iwasaki told Medscape Medical News.

Indeed, Pellini and colleagues pointed out that responses to vaccines against influenza, hepatitis B, and rabies are also reduced in persons with obesity compared to lean individuals.

They said, however, that it was especially important to study the effectiveness of COVID-19 vaccines in people with obesity because obesity is a major risk factor for morbidity and mortality in COVID-19.

"The constant state of low-grade inflammation, present in overweight people, can weaken some immune responses, including those launched by T-cells, which can directly kill infected cells," the authors noted.

Findings Reported in British Newspapers

The findings of the Italian study were widely covered in the lay press in the United Kingdom, with headlines such as, "Pfizer vaccine may be less effective in people with obesity, says study"[5] and "Pfizer vaccine: overweight people might need bigger dose, Italian study says." In tabloid newspapers, some headlines were slightly more stigmatizing.

The reports did stress that the Italian research was published as a preprint and has not been peer reviewed, or "is yet to be scrutinized by fellow scientists."

Most made the point that there were only 26 people with obesity among the 248 persons in the study.

"We always knew that BMI was an enormous predictor of poor immune response to vaccines, so this paper is definitely interesting, although it is based on a rather small preliminary dataset," Danny Altmann, a professor of immunology at Imperial College London, told The Guardian newspaper.

"It confirms that having a vaccinated population isn't synonymous with having an immune population, especially in a country with high obesity, and emphasizes the vital need for long-term immune monitoring programs," he added.

Antibody Responses Differ by BMI, Age, and Sex

Researchers in the Italian study assigned the participants -- 158 women and 90 men -- to receive a priming BNT162b2 vaccine dose with a booster at day 21. They collected blood and nasopharyngeal swabs at baseline and 7 days after the second vaccine dose.

After the second dose, 99.5% of participants developed a humoral immune response; one person did not respond. None tested positive for SARS-CoV-2.

Titers of SARS-CoV-2 binding antibodies were greater in younger than in older participants. There were statistically significant differences between persons aged ≤ 37 years (453.5 AU/mL) in comparison with persons aged 47 to 56 years (239.8 AU/mL; P = .005), persons aged ≤ 37 years vs persons aged > 56 years (453.5 vs 182.4 AU/mL; P < .0001), and persons aged 37 to 47 years vs persons aged > 56 years (330.9 vs 182.4 AU/mL; = .01).

Antibody response was significantly greater for women than for men (338.5 vs 212.6 AU/mL; P = .001).

Humoral responses were greater in persons of normal-weight BMI (18.5 to 24.9 kg/m2; 325.8 AU/mL) and persons of underweight BMI (<18.5 kg/m2; 455.4 AU/mL) compared with persons with pre-obesity, defined as BMI of 25 to 29.9 kg/m2 (222.4 AU/mL), and persons with obesity (BMI ≥ 30 kg/m2; 167 AU/mL; P < .0001). This association remained after adjustment for age (P = .003).

"Our data stresses the importance of close vaccination monitoring of obese people, considering the growing list of countries with obesity problems," the researchers noted.

Hypertension was also associated with lower antibody titers (= .006), but that lost statistical significance after matching for age (= .22).

"We strongly believe that our results are extremely encouraging and useful for the scientific community," Pellini and colleagues concluded.

The authors have disclosed no relevant financial relationships. Iwasaki is a cofounder of RIGImmune and is a member of its scientific advisory board.

Study Highlights

  • The study population comprised healthcare workers at one hospital in Italy who were presenting for the Pfizer-BioNTech COVID-19 vaccine. All participants were between ages 18 and 75 years, and individuals with evidence of current or previous SARS-CoV-2 infection or a history of possible immunosuppression were excluded.
  • Participants received 30 µg/0.3 mL dose of the vaccine at the outset of the study and then another dose 21 days later.
  • Investigators collected blood and a nasopharyngeal samples before the first vaccine dose and 7 days after the booster dose. Researchers collected sera from adults with known COVID-19 to compare immunoglobulin G (IgG) antibody levels against S1/S2 antigens of SARS-CoV-2 with those of vaccinated participants.
  • 248 healthcare workers participated in the study. 63.7% of cohort were women, and the median age was 47 years.
  • None of the participants had a positive polymerase chain reaction test for SARS-CoV-2 before or after vaccination.
  • The antibody geometric mean concentrations after vaccination and among the cohort who provided convalescent sera after COVID-19 infection were 285.9 AU/mL and 39.4 AU/mL, respectively (P < .0001).
  • 99.5% of vaccine recipients were considered to have responded after the vaccine. Only one participant did not.
  • There was a fairly linear decline in immune response from participants aged < 37 years to groups aged 37 to 47 years, 47 to 56 years, and more than 56 years.
  • The antibody geometric mean concentrations after vaccination among women and men were 338.5 AU/mL and 212.6 AU/mL, respectively (P = .001).
  • The other major variable associated with a reduced immune response to the vaccine was overweight or obesity vs underweight or normal weight.
  • The presence of hypertension failed to affect vaccine response in adjusted analysis.

Clinical Implications

  • The COVID-19 mRNA vaccines appear to have efficacy around 80% against COVID-19 after a single dose, but it is unclear how long this protection might last.
  • In the current study by Pellini and colleagues, older age, male sex, and overweight/obesity were associated with a reduced IgG response after application of an mRNA vaccine against COVID-19.
  • Implications for the healthcare team: The healthcare team should continue to emphasize routine protective measures such as physical distancing and mask wearing after administration of the COVID-19 vaccine. This advice might particularly be important among men, older adults, and persons with overweight/obesity.

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