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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; P = .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 (P = .006), but that lost statistical significance after matching for age (P = .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.

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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