Reply to "How important is the second dose of the COVID-19 mRNA vaccine?"

To the Editor:

We thank Liu for a thoughtful commentary on recent guidance for coronavirus disease 2019 (COVID-19) vaccination. , Liu raises several important points that highlight uncertainties surrounding the COVID-19 vaccination effort, suggesting that for some patients who experience a severe allergic reaction to a first mRNA vaccine dose, a second vaccine dose may be deferred or delayed in light of limited evidence demonstrating good short-term efficacy of a single dose. , 4, 5, 6 Our understanding continues to rapidly evolve on this topic. For example, a recent study from the Sheba Medical Centre reported an 85% (95% CI, 71%-92%) reduction in symptomatic COVID-19 cases 15 to 28 days after the first dose of the Pfizer-BioNTech vaccine. This reduction in symptomatic COVID-19 infection is improved from an original estimate for first-dose vaccine efficacy of 52.4% reported by Polack et al, and may differ as a result of timing of the measurement. When considering the ratio of confirmed cases of COVID-19 illness in active versus placebo groups from Polack et al, Pfizer-BioNTech vaccine efficacy has been estimated at 92.6% beginning 14 days after dose 1 to before dose 2. Indeed, this rate is similar to the first-dose efficacy rate of 92.1% reported for the Moderna vaccine. , Still, uncertainty remains regarding single-dose mRNA vaccine protection, as a recent population-based Israeli study including 596,618 vaccinated persons estimated single-dose effectiveness against documented infection at 14 to 20 days at 46% (95% CI, 40%-51%) for the Pfizer-BioNTech vaccine, with estimates of protection reaching 74% (95% CI, 56%-86%) for hospitalization and 72% (95% CI, 19%-100%) for preventing death.

It must be acknowledged that the duration of single-dose mRNA vaccine efficacy is presently unknown. Indeed, even the longer-term efficacy of the full COVID-19 mRNA vaccine series is unclear, and the question of whether or not to routinely defer second vaccine doses in an effort to more rapidly mobilize first vaccine doses to combat the COVID-19 pandemic has been a subject of debate. Given that all COVID-19 vaccine products remain unlicensed and are currently administered under emergency use authorizations (EUA), it may be reasonable to assume that administration per EUA guidance would be optimal. Although, now more than ever, it is important to realize the good is not the enemy of the perfect. Assuming durable high first-dose mRNA vaccine protection is achievable, it could be reasonable to defer a second dose in a patient at high risk for COVID-19 mRNA vaccine anaphylaxis, though this remains a difficult decision to contemplate, rife with uncertainty from widely ranging preliminary estimates regarding the incremental benefit of the fully recommended vaccination series. Recent modeling suggests that deferral of a second COVID-19 mRNA vaccine dose could leverage optimal health and economic outcomes when durable first-dose protection is very high and rates of vaccine anaphylaxis are significantly elevated above baseline risk. For example, assuming durable first-dose protection reaches 90% and a second dose offers only 5% protection, second-dose deferral would be cost-effective if anaphylaxis risk exceeded 0.13%; this frequency is much greater than the risk of anaphylaxis reported in the general population but may be lower than the risk perceived by the allergist-immunologist evaluating a patient after anaphylaxis with a first dose.10, 11, 12, 13 However, at lower rates of first-dose protection, the importance of a second dose may become more significant, and deferral may cause more harm than benefit, even in patients with a risk of COVID-19 mRNA vaccine anaphylaxis well above that of the general population. As an alternative to a second mRNA vaccine dose, guidance has been suggested that a single dose of a COVID-19 viral vector (ie, Janssen) vaccine may be considered at a minimum interval of 28 days from the mRNA dose in persons with a contraindication to a second COVID-19 mRNA vaccine dose. In patients with a contraindication to a COVID-19 mRNA vaccine (considered a precaution to the COVID-19 viral vector vaccine), allergist-immunologist referral should be considered and such administration should occur under the supervision of a provider capable of managing anaphylaxis.

Liu has provided valuable insight into a complex question of second-dose COVID-19 mRNA vaccine deferral. Such an option, as part of shared decision making with the patient, would require careful consideration and would be a highly contextual decision, conditional on a rapidly evolving understanding of best vaccination practices and careful values clarification on behalf of the informed patient. Although most patients referred for a possible vaccine reaction will be able to receive a second vaccine dose safely, for those at very high relative risk for anaphylaxis, the decision to defer or forego the second dose could be a reasonable option to discuss, if indeed protection from a first dose is reliable in the longer-term. Still, for greatest efficacy, providing vaccinations as recommended in each EUA would be preferred if possible. Information on durability of first-dose responses overall, as well as in those who have had mRNA vaccine anaphylaxis or previous COVID-19, and the local availability of additional COVID-19 vaccine options , will also help guide these decisions.