By Joseph F. John, Jr., MD, FACP, FIDSA, FSHEA

Dr. John is Professor of Medicine, Medical University of South Carolina, Charleston.

Dr. John reports no financial relationships relevant to this field of study.

Synopsis: The immunogenicity of trivalent influenza vaccine is attenuated by the administration of A(H1N1)pdm09 4 months before, an effect partially overcome by the presence of an adjuvant in the former.

Source: Roy-Ghanta S, Van der Most R, Li P, Vaughn DW. Responses to A (H1N1)pdm09 influenza vaccines in participants previously vaccinated with seasonal influenza vaccine: A randomized observer-blind, controlled study. J Infect Dis 2014;210:1419-1430.

There was an H1N1 influenza pandemic in 2009, which caused nearly 20,000 deaths. Several H1N1 vaccines were developed in response to the epidemic. Because of the eruptive behavior of H1N1 viruses, there is a need to understand the timing of and response to H1N1 vaccines, particularly in relation to the routine use of multivalent seasonal influenza vaccines.

These investigators from Glaxo Smith Kline (GSK) in Pennsylvania and Belgium knew that response to the H1N1pdm09 vaccine was dependent, to a degree, on the prevaccination serostatus of the population under study. In particular, there has been some evidence published that recipients of trivalent influenza vaccine (TIV) may have altered responses to subsequent H1N1 vaccine, either adjuvanted or non-adjuvanted. The observed decreased response to subsequent H1N1 vaccine alludes to the doctrine of original antigenic sin first published about 50 years ago (J Exp Med 1966:124:331-45): Exposure to a novel virus after exposure to a closely related strain may decrease the response to the subsequent exposure. Adjuventation of the priming vaccine may reduce the immune interference and allow a great response secondary [TO?] exposure.

This study aimed to determine the response to an adjuvanted or non-adjuvanted H1N1 vaccine when given after TIV or a placebo. The H1N1 vaccines were given 4 months after the TIV. An assortment of immune responses were determined. Vaccines were prepared at GSK in Quebec, Canada. The placebo was phosphate-buffered saline. Vaccines were mixed with either phosphate buffered saline (PBS) or the adjuvant known as AS3A. The design was to give TIV followed by adjuvanted or non-adjuvanted H1N1 (Groups A and B), or placebo followed by adjuvanted or non-adjuvanted (Groups C and D).

Of the 171 screened participants, 133 were vaccinated. Only 99 completed the study through day 507. Responses were measured in rates of a good antibody response: rates of memory B-cell responses, rates of CD4 cell responses, and rates of CD8 cell responses. There were no CD8-cell responses.

The best response both antibody and cellular came in the group given a placebo (fake TIV) followed by adjuvanted H1N1. That is, prior TIV produced reduced antibody and CMI responses to H1N1. Adjuvanted H1N1 tended to overcome the TIV vaccine interference. For specific CD4 response markers, the responses were stronger for IL-2 and CD40L than for TNF-alpha, interferon-gamma.


The data set for this study is very large and there were supplemental data. Yet the discussion, as in many excellent papers, is quite short. It emphasizes that response to a vaccine based on a pandemic H1N1 strain may be diminished by prior seasonal multivalent vaccine even though the second vaccine is administered 122 days after the first vaccine. This diminished response includes humoral and cellular responses, both of which may be needed for protection against subsequent influenza infection through their individual responses or through assisted responses, i.e., CD4 cells may help B-cell antibody response. Adjuvants may suppress the effect of the first vaccine when the first vaccine diminishes the response to the second vaccine.

These conclusions are disquieting because they are counterintuitive. Our intuitive sense is that consecutive vaccines with similar pathogens should be additive. Indeed, we have come to accept that boosters produce augmented humoral and cellular responses. Yet the message from this study is that unless the serial vaccines use identical or very closely related strains, we cannot discount interference from the initial vaccine.

Many different influenza vaccines are available. Unfortunately, to determine the precise response to serial administration of influenza vaccines requires intense complex laboratory methods, as demonstrated in the present study by GSK. Even when the vaccines are given as much as four months apart, there may be antagonism exerted by the first response against the second response, as was seen in this study.

In summary, caution must reign when giving advice about the use of second influenza vaccines. Depending on the similarity or dissimilarity of the influenza vaccine strains, there may be a surprise of a diminished response to the second influenza vaccine.