A study by scientists at the U.S. Food and Drug Administration (FDA) investigated the role of the adjuvant, MF59, on immune response in individuals who were previously vaccinated (known as “priming”) against H5N3 influenza virus at least six years earlier. Specifically, they investigated whether the adjuvant enhanced the ability of an H5N1 influenza vaccine to produce increased amount of antibodies and against more than one type of H5 avian influenza virus.
Adjuvants are incorporated into some vaccine formulations to enhance or direct the immune response of the vaccinated individual. MF59 is an oil-in-water emulsion and is not contained in any currently FDA-approved vaccines.
Because influenza viruses can change, a new virus can emerge suddenly with the ability to spread from person-to-person around the world and cause severe disease. This rapid spread, known as a pandemic, is partly due to the fact that most people do not have pre-existing immunity against the new virus. The impact or severity tends to be higher in pandemics than for seasonal influenza in part because of the much larger number of people in the population who lack pre-existing immunity to the new virus. When a large portion of such a population is infected, even if the proportion of those infected that go on to develop severe disease is small, the total number of severe cases can be quite large. A vaccination strategy that could elicit long-term immunity with a probability of some cross-protection against emerging strains would be valuable and have an impact on global public health.
The current research is an extension of a 2007 study demonstrating the ability of an H5N1 vaccine combined with the adjuvant MF59 to trigger antibody protection against various strains of that avian influenza virus. That study included the following three groups of people: 1) individuals who received a vaccine adjuvanted with MF59 in 1999 or 2001 against a particular strain of H5N3; 2) individuals who received an unadjuvanted vaccine in 1999 or 2001 against that same strain of H5N3; 3) unprimed individuals, i.e., those who had not received an initial vaccine against the H5N3 influenza virus strain.
The H5N3 and H5N1 strains are different enough to be assigned to two different “clades” and are not expected to cross-protect. The 2007 study participants were given two doses of the H5N1 vaccine adjuvanted with MF59, and in those individuals who were previously vaccinated; it is called a “booster” dose. The vaccine triggered substantial antibody production against the H5N1 virus in those who had previously received the adjuvanted vaccine against H5N3. The boost was weaker in people who had received an unadjuvanted H5N3 vaccine and in those who had not been primed with the initial H5N3 vaccine the antibody response was poor. In addition, individuals who had been primed with adjuvanted H5N3 vaccine before receiving the adjuvanted H5N1 vaccine produced neutralizing antibodies against a variety of different strains of H5N1 influenza. This suggested that such a prime-boost strategy with an adjuvanted vaccine could offer protection against newly emerging avian influenza varieties of H5N1.
This new study investigated the antibody response triggered by the earlier priming with H5N3 vaccine and the impact of MF59 adjuvant during priming. Scientists from FDA’s Office of Vaccines Research and Review did further analysis of the study participants’ blood (serum) samples from 2007 to determine the quality of the antibodies and whether long-term memory B cells were present. Memory cells are those that have been exposed to antigens and can then respond more readily when the immune system encounters those same antigens again.
The FDA scientists used a technique called surface plasmon resonance to measure how readily antibodies bound to two different domains (areas) on the hemagglutinin (HA) protein on the surface of influenza viruses. Influenza viruses use HA to attach to target cells in the respiratory tract to infect an individual. Vaccines that prevent influenza trigger production of antibodies against HA. The globular head domain, called HA1, binds directly to proteins on the cell called receptors; the stalk domain, called HA2, supports HA1 and is attached to the virus. The study demonstrated that an improved memory response against H5N1 vaccine virus strain in individuals exposed to H5N3 virus 6 or 8 years earlier strongly correlated with post-vaccination serum antibody binding to HA1 from the boosting H5N1 virus strain. Specifically, the antibody binding to HA1 of H5N1 in MF59-H5N3 vaccine-primed individuals was significantly stronger compared to antibodies of those individuals who had not been primed and those who were primed with the H5N3 vaccine without adjuvant.
Importantly, the antibodies from individuals primed with the adjuvanted H5N3 vaccine also bound more efficiently to HA1 proteins on a variety of different H5N1 influenza virus strains and were more effective in neutralizing these influenza viruses.
Overall, the findings show that antibodies in individuals primed with the adjuvanted H5N3 vaccine developed strong HA1-targeting neutralizing antibodies against not only the H5N1 strain included in the later vaccine boost, but also against other H5N1 influenza virus strains.
The findings of the current study offer an explanation for the increased amount of effective antibodies and suggest that such antibodies, triggered by the mismatched H5 influenza vaccine prime-boost strategy using MF59 as the adjuvant could provide at least some protection against a variety of H5N1 avian influenza virus strains with pandemic potential.
Heterologous Prime-Boost Vaccination with MF59-Adjuvanted H5 Vaccines Promotes Antibody Affinity
Maturation towards the Hemagglutinin HA1 Domain and Broad H5N1 Cross-Clade Neutralization
April 2014 | Volume 9 | Issue 4 | e95496
Surender Khurana1*, Elizabeth M. Coyle1, Milena Dimitrova1, Flora Castellino2, Karl Nicholson3,
Giuseppe Del Giudice2, Hana Golding1*
1 Division of Viral products, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA), Bethesda, Maryland,
United States of America,
2 Novartis Vaccines and Diagnostics Srl, Sienna, Italy
3 Department of Infection, Inflammation, and Immunity, Maurice Shock Medical Sciences Building, University of
Leicester, Leicester, United Kingdom