COVID-19 vaccination of the immunocompromised—an n-of-1 observational study
February 2022—The CDC published on Nov. 5, 2021 a report indicating that immunocompromised persons receiving SARS-CoV-2 mRNA vaccines should receive three doses and a booster (MMWR Morb Mortal Wkly Rep. 2021;70[44]:1553–1559). The following n-of-1 observational study suggests that an immunocompromised nonresponder to mRNA vaccine may indeed respond to a second series of SARS-CoV-2 mRNA vaccine.
A 74-year-old male with chronic lymphocytic leukemia in remission since 2007 received two standard doses of Pfizer mRNA vaccine according to established protocol. This patient with hypogammaglobulinemia requires intravenous immune globulin, 35 g, every 10 weeks. Using the semiquantitative SARS-CoV-2 neutralizing antibody test (Advia Centaur, Siemens), no evidence of seroconversion was detected on two occasions, i.e. no antibody was detected 13 days after the second vaccine dose, and again 142 days after the second vaccine dose. These results indicate a nonresponder to the COVID-19 mRNA vaccine.
On Aug. 20, 2021, when booster vaccinations became available, a third dose of Pfizer mRNA vaccine was obtained. Five days later, the antibody to neutralizing spike protein remained negative. This test was repeated on the same Siemens platform 26 days after the booster vaccination and was positive for the first time. This semiquantitative test for antibody to neutralizing spike protein is reported in “units” from 1,000 to greater than 140,000, giving an estimate of the quantity of antibody present. This first positive result was reported as 4,484 units.
These findings suggest a pattern in which a nonresponder to the standard two-dose regimen subsequently developed neutralizing antibody as a primary response to the booster. It was reasoned that a fourth dose of mRNA vaccine would represent the completion of a second attempt of the complete two-dose regimen. This is not unprecedented in that repeating the three-dose vaccination schedule for hepatitis B nonresponders is common.
In this case, a fourth dose of Pfizer vaccine administered on Oct. 13, 2021 had the same concentration of mRNA as the previous three doses. Also, the fourth vaccine dose was administered 54 days after the third dose instead of the desired follow-up dose at 28 days. The antibody to spike protein was retested on the day of the fourth dose and again five days later with positive results of 4,237 and 4,295 respectively. This represents insignificant change from the presumed primary response of 4,484 units first detected on Sept. 15, 2021. On Nov. 22, 2021, 39 days after the fourth vaccination, the antibody to spike protein was positive at 12,424 units. Further study is needed to assess the value of repeat vaccination in nonresponders.
The study also suggests there may be value in testing particular patient populations for neutralizing antibody to SARS-CoV-2. Correlation between antibody titer and protection has been reported in Israeli health care workers (Bergwerk M, et al. N Engl J Med. 2021;385[16]:1474–1484). However, the value of neutralizing antibody to SARS-CoV-2 and the role of cellular immunity are incompletely understood. Nonetheless, this n-of-1 observational study presents hope to those who did not respond to the initial two doses of mRNA vaccine.
Jerry Kolins, MD
Medical Director of Laboratories
Palomar Medical Center Escondido
Escondido, Calif.
Send letters to editor at srice@cap.org.