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Researchers at EpiVax and University of Rhode Island explain H7N9 influenza vaccine failure:

Pathogen developed ‘Immune Camouflage’ to hide from human immune response

The avian influenza A(H7N9) virus has been a major concern since the first outbreak in China in 2013. Due to its high rate of lethality and pandemic potential, H7N9 vaccine development has become a priority for public health officials. However, candidate vaccines have failed to elicit strong immune responses necessary to protect from infection. A new study published in Human Vaccines & Immunotherapeutics[1] has revealed that it might be due to immune camouflage (see full text on line – open access – at this link).

Experts are worried about the new avian flu, because of the high mortality rate that is associated with cases in humans. Vaccines against the new strain have been poorly effective: In stark contrast with recent vaccines for a type of seasonal influenza (H1N1), unadjuvanted H7N9 vaccines have generated very low immune responses without adding strong adjuvants. Seroconversion rates of only 6% and 15.6% have been reported in Phase I clinical trials[2],[3],[4] (as compared to 89% for similar unadjuvanted seasonal H1N1 subunit vaccines[5]).

Computer tools developed by senior author Prof. Anne S. De Groot MD, Director of Institute for Immunology and Informatics at the University of Rhode Island, and CEO at EpiVax, Inc. were able to predict the efficacy of the new vaccines, long in advance of the clinical trials. “Our original prediction that H7N9 vaccines would have low efficacy was made before any clinical data were available,” says De Groot. “It turns out that we were absolutely correct. By comparison with H1N1 and H3N1, H7N9 vaccines are far less immunogenic.”

One of the ways by which the immune system detects infection is by presenting short peptides derived from the pathogen to T cells, which distinguish between foreign and self antigens. A new study published by De Groot and colleagues shows that the H7N9 hemagglutinin (HA) surface protein has evolved a set of mutations that make it similar to human proteins, and the presented peptides thus resemble self antigens. The H7N9 influenza strain appears to effectively camouflage itself from the immune system.

Prof. De Groot’s research team has developed a computational tool, JanusMatrix, which is capable of determining whether a given viral protein is similar to any human protein in residues relevant for antigen presentation. “JanusMatrix looks at both ‘faces’ of T-cell epitopes. It starts by looking at the face that binds to HLA or MHC – the downward facing amino acids that bind into the MHC binding pockets. Having determined that a peptide can bind to a specific MHC, the program then looks at the T-cell receptor face (TCR face) and looks in a database of pre-parsed peptides from the human genome that have been identified as binding to the same MHC, for peptides that have the same TCR-facing amino acids.”

It turns out that, in addition to having low T cell epitope content, HA from H7N9, but not from other investigated influenza strains, shows high similarity to several endogenous proteins.

The immune-camouflage hypothesis was tested by challenging peripheral blood mononuclear cells from naïve donors with H7N9-derived peptides. Remarkably, the more the peptide resembled a self-antigen, the less it was able to elicit a T-cell response. In addition, the predicted human-like antigens expanded and activated regulatory T cells that are responsible for immune suppression when endogenous peptides are presented, providing further support for the hypothesis.

“It appears that this new mechanism of immune escape may be common to quite a few human pathogens,” says Prof. De Groot. “We are working on validating several other peptides, some from common seasonal strains of influenza and some from pathogens like HIV and M. tuberculosis that do live for a long time inside their hosts.”

H7N9 influenza has infected more than 670 cases and led to more than 230 deaths, according to the Centers for Disease Control. These findings could facilitate the development of an effective vaccine and impact vaccine research in general. “It could well explain why some candidate vaccines for pathogens that have co-evolved with human beings – like TB and HIV – do not work so well. It also suggests that ‘tweaking’ pathogen proteins to remove those camouflaging sequences would result in better, more effective vaccines,” concludes Prof. De Groot.

 

About H7N9 (from Wikipedia) https://en.wikipedia.org/wiki/Influenza_A_virus_subtype_H7N9

H7N9 is a bird flu strain of the species Influenza virus A (avian influenza virus or bird flu virus). H7N9 virus was first reported to have infected humans in March 2013, in China. January 2014 brought a spike in reports of illness with 96 confirmed reports of disease and 19 deaths. As of April 11, 2014, the outbreak’s overall total was 419, including 7 in Hong Kong, and the unofficial number of deaths was 127.

About EpiVax

EpiVax, Inc. is a privately-held Providence, Rhode Island biotechnology company focused on the development of vaccines and biologic products for human and animal diseases. The company applies its immunoinformatics toolkit to design “biobetter” biologics and vaccines, and to screen biologics for immunogenicity so as to reduce adverse effects in the clinic. CEO De Groot was recently named one of the 50 most influential persons in the field of vaccines. For more information visit http://www.epivax.com.

 

Useful Links

 

H7N9 Manuscript on line: http://www.tandfonline.com/doi/full/10.1080/21645515.2015.1052197

JanusMatrix Tool http://bit.ly/JanusMatrix
EpiVax Cloud-based Vaccine Toolkit http://bit.ly/iVAX_2015

Institute for Immunology and Informatics http://www.immunome.org

 

[1] Liu R, Moise L, Tassone R, Gutierrez AH, Terry FE, Sangare K, Ardito MT, Martin WD, De Groot AS. H7N9 T-cell epitopes that mimic human sequences are less immunogenic and may induce Treg-mediated tolerance. Hum Vaccin Immunother 2015; 11(9):2241-52. doi: 10.1080/21645515.2015.1052197

[2]. Media Release Novartis 2013; http://www.novartis.com/newsroom/media-releases/en/2013/1743124.shtml

[3]. Fries LFSmith GEGlenn GM. N Engl J Med 2013; 369:2564-6.

[4] Bart, Sci Transl Med. 2014 Apr 30;6(234):234ra55

[5]. Griffin MRMonto ASBelongia EATreanor JJChen QChen JTalbot HKOhmit SEColeman LALofthus G, et al. Effectiveness of non-adjuvanted pandemic influenza A vaccines for preventing pandemic influenza acute respiratory illness visits in 4 U.S. communities. PLoS One 2011; 6:e23085.