Why some people tolerate the second dose of a vaccine but not the first dose

Vaccine adverse reaction investigations typically rest on the premise that every dose of a vaccine has the potential to cause adverse reactions in sensitive populations. In the case of an anaphylaxis reaction to messenger RNA (mRNA) vaccines against coronavirus disease 2019 (COVID-19), the investigation quickly focused on polyethylene glycol, which is present in every dose of these vaccines.¹ To date, no definitive conclusion has been reached. On the contrary, a recent study published in this journal suggests that the polyethylene glycol skin test has little use in assessing allergic reactions to these vaccines.² It is perhaps time to consider factors other than vaccine ingredients, such as the quality of individual vaccine doses.³

There are now multiple reports on people who developed adverse reactions, including anaphylaxis, to the first dose of mRNA COVID-19 vaccines but tolerated the second dose.4, 5, 6, 7 For example, 1 retrospective study reported that 159 people who developed immediate reactions to the first dose of mRNA COVID-19 vaccines, including 19 cases of first-dose anaphylaxis, all tolerated the second dose.⁴ At least 5 people who developed first-dose anaphylaxis tolerated the second dose without premedication.

One possible explanation for this observation is some adverse reactions were caused by defective doses of vaccines. Here, a defective dose means its critical quality attributes are outside the acceptable range. When the product defect rate is low, it is unlikely that the same person will receive 2 bad doses. This may be the reason why some people tolerate the second dose of a vaccine but not the first dose, and vice versa.

As of January 18, 2021, the anaphylaxis rate for Pfizer and Moderna mRNA COVID-19 vaccines in the United States was 4.7 cases/million doses administered and 2.5 cases/million doses administered, respectively.⁸ Unless the defect rate of these 2 vaccines at vaccination sites is known to be much lower than the anaphylaxis rate, the possibility that some anaphylaxis cases were caused by defective doses cannot be excluded. It is unrealistic to expect any pharmaceutical product to have a zero defect rate by the time they are administered. Pharmaceutical product defects may occur during manufacturing, which is not very precise,⁹ or during distribution, in which mishandling such as cold chain breaches may happen.¹⁰

Whereas adverse reactions caused by defective doses may occur to any pharmaceutical product, the 2-dose regimen of mRNA COVID-19 vaccines offers an opportunity to test these two possibilities more readily. If anaphylaxis is primarily caused by good-quality vaccine doses (most in a batch), then the probability of 1 person experiencing anaphylaxis twice would be on the order of 4.7/10⁶ and 2.5/10⁶ doses for the 2 mRNA COVID-19 vaccines—that is, a few per million. However, if anaphylaxis is primarily caused by bad-quality vaccine doses (few in a batch), then the probability of 1 person experiencing anaphylaxis twice would be on the order of (4.7/10⁶)² and (2.5/10⁶)² for the 2 mRNA COVID-19 vaccines—that is, a few per trillion. When data become available, these 2 possibilities may be distinguished by the number of vaccinees who experienced anaphylaxis twice divided by the total number of vaccinees who received 2 doses.