After receiving immunizations, fever is part of the body's normal inflammatory process. In many cases, acetaminophen (paracetamol) is administered to relieve possible risk of high fever or febrile convulsions in children after routine infant vaccinations. An article in this week's edition of The Lancet reports that prophylactic acetaminophen does indeed reduce post-vaccination fever. However, it also reduces the child's response to some of the vaccine antigens. As a result, use of prophylactic acetaminophen can no longer be routinely recommended in this situation. The article is the work of Professor Roman Prymula, University of Defence, Hradec Kralove, Czech Republic, and colleagues.

The authors conducted two randomized controlled trials in the study. The first one focused on the time of initial childhood vaccinations. The second one considered the time of booster injections. The vaccinations were the routine vaccinations accessible to children in developed nations, to offer protection against pneumococcal disease, Haemophilus influenzae type b, diphtheria, tetanus, whooping cough, hepatitis B, polio, and rotavirus. In ten centers in the Czech Republic, infants were randomly assigned to receive three prophylactic acetaminophen (paracetamol) doses every 6 to 8 hours in the first 24 hours after vaccination (226 infants). The control group of 233 infants did not receive acetaminophen. The primary aim of the study was the reduction in fever of 38oC (100.4 F) or higher. The secondary aim was to analyze immunogenicity of the administered vaccines.

After initial vaccinations, results indicated that a lower proportion of infants in the acetaminophen group had temperatures above 38oC compared to the control group (42 percent compared to 66 percent respectively). After booster vaccinations, similar results were observed (36 percent in prophylactic acetaminophen group compared to 58 percent in control group). Antibody geometric mean concentration is a measure of the immune system's response to a vaccine.Geometric mean concentrations (GMCs) were significantly lower in the acetaminophen group than in the control group, for antibodies against the pneumococcal serotypes contained in the vaccine, Haemophilus influenzae type b, diphtheria and tetanus toxoids, and for one of the whooping cough antibodies. After booster vaccinations, lower antibody GMCs persisted in the acetaminophen group for tetanus toxoid and most pneumococcal serotypes.

The authors explain: "To our knowledge, such an effect of prophylactic acetaminophen on postimmunisation immune responses has not been documented before... the interference of paracetamol on antibody responses could result from the prevention of inflammation."

The researchers assume that prophylactic acetaminophen could reduce immune responses. They indicate it interferes with the early phase of post-vaccination immune reactions that require interaction between different cells of the immune system (dendritic cells, T cells, and B cells). But for this hypothesis to be accurate, acetaminophen should alter the responses only if administered at the time of or early after immunisation. The analysis of the information is corroboration. In addition, the researchers analyzed ten earlier studies. The findings supported the hypothesis that acetaminophen maximally interferes with vaccine responses if administered early. However, if used therapeutically once fever and the corresponding inflammatory signals have already been established, its effect can be expected to be minor.

Acetaminophen is an antipyretic drug which reduces body temperature in response to situations such as fever.

The authors write in conclusion: "The clinical relevance of these immunological findings is unknown and needs further assessment. Prophylactic administration of antipyretic drugs at the time of vaccination should nevertheless no longer be routinely recommended without careful weighing of the expected benefits and risks."

In an associated comment, Dr Robert T Chen, of the Centres for Disease Control and Prevention, Atlanta, GA, USA, and colleagues remark: "In today's study, the high proportion of vaccine recipients reaching seroprotective antibody levels suggests that the effect of paracetamol for any given individual might be small; further assessment at the individual level, such as whether or not paracetamol increases the proportion of vaccine non-responders, is warranted. However, a larger question is the extent to which paracetamol might reduce population protection. This point has implications, especially for Haemophilus influenza and pneumococcus, for which higher and sustained antibody concentrations are needed to interrupt the carrier state and reduce transmission within the population, and for pertussis, the bacterial vaccine-preventable disease that is the least well controlled."

"Effect of prophylactic paracetamol administration at time of vaccination on febrile reactions and antibody responses in children: two open-label, randomised controlled trials"
Roman Prymula, Claire-Anne Siegrist, Roman Chlibek, Helena Zemlickova, Marie Vackova, Jan Smetana, Patricia Lommel, Eva Kaliskova, Dorota Borys, Lode Schuerman
Lancet 2009; 374: 1339-50
The Lancet

Stephanie Brunner (B.A.)