Evolution of influenza specific pre-existing immunity over time

Influenza is a major public health problem as it causes 3 to 5 million cases of severe illness and 290 000 to 650 000 respiratory deaths per year worldwide according to WHO updated 2019 data. Type A and type B influenza viruses cause a respiratory tract infection which is characterized by sudden onset of symptoms. It can be fatal especially in young children, the elderly, and chronically ill people which are the main groups at risk. Vaccination remains the best strategy to prevent influenza infections. However, current vaccines show a rather low effectiveness of about 40-60% depending on the virus strain and age of the vaccinated person [1,2]

One factor contributing to the low vaccine effectiveness is the high variability of influenza virus. Point mutations affecting the epitopes on the viral hemagglutinin (HA) lead to (partial) escape of the virus from pre-existing antibodies; this phenomenon called ‘antigenic drift’ facilitates the annual influenza epidemics. In addition, occasional transmission of new virus subtypes from animal species to humans is associated with so called ‘antigenic shift’ (a complete change of HA) and can give rise to large scale pandemics.

Protection from influenza virus is provided mainly by neutralizing antibodies directed against HA which are able, by definition, to interfere with the entry of virus particles into the cells of the upper respiratory tract. These antibodies can be detected through the so-called microneutralization assays (MNA). Neutralizing antibodies tend to be very strain specific; cross-neutralizing antibodies (thus antibodies which can neutralize other virus strains than the one they were raised against) are not very common. Next to neutralizing antibodies influenza infection and vaccination also induce non-neutralizing antibodies which nowadays receive more and more attention. Non-neutralizing antibodies often target more conserved epitopes of influenza virus, unlike neutralizing antibodies which are mostly directed against highly variable epitopes. In a recent review from our group we describe that three effector mechanisms that can be engaged by non-neutralizing antibodies are known to contribute to protection against influenza virus. These effector mechanisms are antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and antibody-dependent complement deposition (ADCD). [3] Non-neutralizing antibodies can be detected through ELISA (Enzyme-Linked Immunosorbent Assay) or through functional assays.

Another phenomenon which seems to affect the response to influenza vaccines is the level of pre-existing immunity. By the age of 6, all children have been exposed to influenza at least once and adults have undergone several infections, both symptomatic and non-symptomatic [2].  How sequential exposures to different influenza virus strains shape the influenza-specific immune response is so far poorly understood. Originally, it was thought that influenza-specific immunity, in particular antibody-mediated immunity, is virus strain-specific and that exposure to a new virus strain would evoke new antibodies optimally fitting this strain. Consequently, vaccines have been designed such that they contain antigens of the virus strains most likely circulating in the following influenza season. [2,4]

However, newer research is beginning to change this picture. There is now convincing evidence that influenza-specific antibodies are to a large extent not strain-specific but can rather react with a number of different strains[4] .This implies that due to immune memory, the immune system of an individual who has undergone several infections or vaccinations with different influenza virus strains in the past will respond in a different way to a new virus strain than the immune system of a young child during its first infection. In individuals with an influenza-experienced immune system, earlier activated B cells rather than new naïve B cells seem to respond most strongly, resulting in antibodies with suboptimal binding affinity to the new strain. This phenomenon is called ‘original antigenic sin’. Indeed, recent research suggests that the influenza virus strain first encountered in life determines to a large extent the response to subsequent influenza infections or vaccinations ( 7,8). Yet, other reports imply that although antibodies to the old strains dominate in the response new antibodies are also produced. According to this ‘antigenic seniority hypothesis’, with each new infection or vaccination the antibody response to influenza viruses in general broadens but the oldest antibodies take the most senior position in the response[5] .

While much has still to be learned, these observations imply that the pre-existing influenza-specific immunity, or influenza immune history, of an individual can strongly impact on her/his response to vaccination. In order to design smart vaccines or vaccination strategies, it is therefore of great importance to get a better insight in the development of and changes in influenza-specific immunity during the life span. This can be achieved by performing longitudinal studies and assessing antibody levels and reactivity with different virus strains in samples from the same individual taken over a number of years[5,6].

In short we are interested in unravelling the mystery of how influenza immunity develops over time on an individual base in order to design better vaccination strategies. With sequentially taken serum samples from individuals belonging to different age cohorts, the LifeLines biobank is uniquely suited for longitudinal studies into the development of influenza-specific immunity during life.