Next on the Influenza Virus Vaccine Horizon: A Slow Releasing Antigen Concept

In a field where vaccination is the cornerstone in reducing morbidity and mortality from seasonal influenza virus infections, it is detrimental that the standard influenza virus vaccines only elicit strain specific immune responses which are susceptible to mismatch in seasons where antigenic drift is prevalent. That is why there is an urgent need to improve influenza vaccines through strategies that induce more robust immune responses with cross-reactive properties. 

Addressing this pressing need, Martin Beukema from the University Medical Center Groningen, the Netherlands, presented a promising strategy during the “Future Vaccination Strategies” session. His approach is rooted in the concept of mimicking the vaccine delivery kinetics of natural infection. The rationale behind this approach is as follows: following a natural infection, antigens have an extended availability resulting in the induction of a more heterosubtypic and robust immune response compared to conventional immunization strategies. Previous studies have already demonstrated that vaccines designed for extended antigen delivery can quantitively enhance the induced immune response. Whether the quality of this induced immune response is improved, however, remained to be investigated. As such, Martin Beukema and colleagues set out the mission to investigate exactly this by immunizing mice daily with an H1N1pdm09 whole inactivated influenza virus (WIV) vaccine for a period of 14, 21 or 28 days. The results indicated that overall, by prolonging the delivery of the WIV a stronger cellular and humoral immune responses could be obtained compared to prime-boost immunization. Notably, extending the antigen delivery to 28 days yielded the highest magnitude of cellular and humoral immune responses, for both hemagglutinin-specific antibodies against homologous, as well as heterologous viruses. Furthermore, an increased level of antibody class-switching to antiviral IgG2a after 28, but not 14 or 21, days of antigen delivery was observed, leading to a more balanced IgG1 and IgG2a immune response. 

One particularly interesting finding included the possibility of a so-called “germinal center (GC) shutdown” after effective induction of cellular and humoral immune responses following prolonged antigen delivery. This GC shutdown was described as an overall decrease in germinal center B cells in the draining lymph nodes of mice while there was an increase in the light to dark zone differentiation. A mechanistic explanation for this phenomenon remains a subject for further exploration. 

While the research is undeniably compelling, a pressing question arises: how can this concept be translated into practical use, given the impracticality of vaccinating individuals for 28 days? The exciting news is that Martin Beukema and his team are currently trying to develop polymers that contain integrated antigen(s) that can be incorporated in the human skin. Following incorporation, the philosophy is that the polymers will gradually degrade, ensuring an extended release of the antigen. Whether they are indeed able to translate this promising concept to the clinic remains to be seen.