The answer to the question of whether antipyretic analgesics have a clinically significant impact on vaccine response has significant public health implications. Although generating a great deal of interest in the topic, the 2009 Prymula study did not answer the question because the acetaminophen-associated antibody blunting that was observed following vaccination still resulted in protective antibody levels. Additionally their follow up study showed a robust antibody response following booster vaccine doses. The studies included in our review reported no significant blunting of the immune response in papers published prior to the 2009 Prymula study, but since that report there have been several studies that have suggested immune blunting. One study showed lower response to a novel influenza strain following vaccination; however the difference was not statistically significant.26 Thus, at this time, there is no clear answer as to whether antipyretic analgesic administration blunts the immune response to a degree that could result in vaccine failure.
The timing of administration of antipyretic analgesics appears to be paramount. In all studies that reported a negative effect on antibody response, the medications were given prophylactically. Interestingly, this effect was not seen when acetaminophen was given only four hours after immunization.6 Additionally, all reported decreases in antibody response occurred only with novel antigen vaccination, with little to no impact observed following booster immunizations. These findings underscore the notion that relationship between antigen exposure and the timing of the medication dosage plays a vital role in modifying the immune response, and this set of observations can direct the focus of future research to explore the underlying mechanism.
The array of vaccine antigens in use today has evolved over the last several decades, and this evolution continues as new vaccines are being developed, and as new technologies and advanced manufacturing techniques become available. Modern vaccines employ more purified proteins as well as novel adjuvant formulations,77 and many older vaccines are being mixed into single dose combination vaccines. However, the increased availability of vaccines means that simultaneous multiple vaccines may be given during the same visit. Do any of these factors come into play to shape the immune response when antipyretics are given? Further work will be needed to elucidate the effects of these changes on vaccine response.
Another intriguing and unanswered question is whether antipyretics exert a negative effect by suppressing a beneficial increase in temperature that could augment vaccine responses. A recent review by Evans et al. illustrated how thermal stress stimulates and augments the innate and adaptive immune responses.78 Given the mixed antipyretic and anti-inflammatory effects of clinically available NSAIDs and other analgesics, studies to examine this question may be difficult to perform in humans, and animal studies using novel compounds and/or in vitro studies may be needed. However, one limitation of in vitro studies is that they may artificially simplify the immune response