F is for Flu (and other pandemic and bioterror preparedness)
14 months have passed since the Commission on the Prevention of Weapons of Mass Destruction Proliferation and Terrorism (WMD commission) predicted that a terrorist event involving a biologic weapon would take place very soon (before 2013). Despite that dire warning, the most recent test of our preparedness – the H1N1 influenza pandemic – highlighted some very important weaknesses in the national WMD preparedness system. According to Graham and Talent, authors of the WMD Report Card published in January 2010, the risk of bioterror has continued to grow.
In fact, the Graham-Talent report card gave the U.S. government an F – stating that the lack of U.S. capability to rapidly recognize, respond, and recover from a biological attack is a failure of potentially devastating proportion. According to the authors, detection and diagnosis capabilities are the first links in the biodefense preparedness chain, followed by: providing actionable information to federal, state, and local leaders and the general public; having adequate supplies of appropriate medical countermeasures; quickly distributing those countermeasures; treating and facilities; protecting the well through vaccines and prophylactic medications; and in certain cases, environmental cleanup. According to the WMD report card, “the United States is seriously lacking in each of these vital capabilities”. Hence the F.
What’s the good news? A thorough review of the nation’s tools for bioterror and pandemic preparedness is about to begin. That review is prompted in part by last fall’s delays in delivery of the pandemic H1N1 vaccine. The review was announced by HHS Secretary Kathleen Sibelius in a speech to the American Medical Association in December, and reinforced by the release of the WMD Report Card in January.
What could be done about the situation immediately? Prioritize the development of vaccines. How could that be done? Use a method for vaccine development called “epitope-driven vaccines”, being pioneered at EpiVax that is fast, efficient, cheap, and safe. In the cancer vaccine field, the methods are well accepted, and number of epitope-driven vaccines have successfully passed preclinical tests and are either currently in Phase I/II clinical trials or trials are soon to be initiated. By contrast, the immunome-derived, epitope-driven vaccine (ID-EDV) approach for bioterror and emerging infectious disease pathogens has been misunderstood and underfunded, and as a consequence, few such vaccines have reached the stage of Phase I or II efficacy trials in humans [[i],[ii]].
As outlined in EpiVax publications, the critical components of a vaccine can be summarized as follows: Immunogen + Adjuvant + Delivery vehicle = Vaccine. Adjuvants and delivery vehicles abound, but immunogens have proven difficult to accelerate, as methods for isolating the critical protein (including egg-based culture for influenza) are – frankly speaking – antiquated. A better method of making “faster vaccines” is to design immunogens directly from the pathogen genomes – the immunome derived epitopes referred to above. The tools for carrying out that task are already available and have been deployed for SARS, H1N1, and a number of other emergent infections (WNV).
The key to rapid vaccine development is a tool called an “epitope mapping algorithm”. These tools have been in existence since the 1980’s, but only recently have they been deployed in conjunction with other vaccine design tools that concatenate the epitopes into a single delivery vehicle, which, when combined with adjuvant, can be tested in challenge models.
Detractors say that the method is unproven; that the number of epitopes required is unknown, and that the algorithms are not accurate. In fact, evidence from animal studies suggests that the number of epitopes required for full protection is a small and definable subset . Careful selection of promiscuous Class II (T helper) epitopes and Class I (Cytotoxic T cell) supertype epitopes can provide greater than 99% coverage of human populations]. An effective ID-ED vaccine for humans may need to include at least 50 Class I and Class II broadly HLA-restricted (promiscuous) epitopes. Another means of improving the immunogenicity of an ID-EDV is to choose epitopes that induce multi-functional T cell responses in human PBMC. Careful selection of vaccine delivery vehicle, route and formulation will improve immunogenicity and may also improve the likelihood of successful protection against disease, and the whole process can be accomplished in months, not years.
Higher-quality, validated vaccine design tools, such as the ones developed by EpiVax over the past 10 years, enable the effective selection of highly immunogenic, vaccine epitopes. The delivery of these epitopes by the right route, in properly designed constructs and effective delivery vehicles, with the right adjuvant is likely to improve immunome-derived epitope-driven vaccine success and lead to significant improvement in the prevention of pandemic spread and improved bioterror preparedness for future generations. Here’s hoping that the HHS and IOM meetings lead to a call for increased funding for “faster” vaccine approaches, and a recognition that the time for immunome-derived, epitope driven vaccines has finally come.
Click here for a slideset that outlines our approach: [FastVax Platform by EpiVax]
Sources of information for this report:
Robert Roos, CIDRAP News, Feb 9, 2010
Graham Talent WMD Report Card
https://www.preventwmd.gov/home/
IOM information on the Feb 22-24 meeting
https://www.iom.edu/Activities/PublicHealth/MedPrep/2010-FEB-11.aspx
Sibelius’s Dec 1 speech announcing plans for the countermeasures program review
https://www.hhs.gov/secretary/speeches/sp20091201.html
Agenda for the Feb 10 NBSB meeting
https://www.hhs.gov/aspr/omsph/nbsb/021010agenda.pdf
Graham Talent Commentary on H1N1 flu response
https://www.washingtonpost.com/wp-dyn/content/article/2010/01/03/AR2010010301812.html
. Eliott SL, Suhrbier A, Miles JJ, Lawrence G, Pye SJ, Le TT, Rosenstengel A, Nguyen T, Allworth A, Burrows SR, Cox J, Pye D, Moss DJ, Bharadwaj M. Phase I trial of a CD8+ T-cell peptide epitope-based vaccine for infectious mononucleosis. J Virol. 2008 Feb;82(3):1448-57. Epub 2007 Nov 21.
. McKinney DM, Skvoretz R, Livingston BD, Wilson CC, Anders M, Chesnut RW, Sette A, Essex M, Novitsky V, Newman MJ. Recognition of variant HIV-1 epitopes from diverse viral subtypes by vaccine-induced CTL.J Immunol. 2004 Aug 1;173(3):1941-50.
. Moutaftsi M, Peters B, Pasquetto V, Tscharke DC, Sidney J, Bui HH, Grey H, Sette A. A consensus epitope prediction approach identifies the breadth of murine T(CD8+)-cell responses to vaccinia virus. Nat Biotechnol. 2006 Jul;24(7):817-9.
. Moise L, De Groot AS. Putting immunoinformatics to the test. Nat Biotechnol. 2006 Jul;24(7):791-2.
. Sette A, Sidney J. Nine major HLA Class I supertypes account for the vast preponderance of HLA-A and –B polymorphism. Immunogenetics. 1999 Nov;50(3-4):201-12.
. Wille-Reece U, Wu CY, Flynn BJ, Kedl RM, Seder RA. Immunization with HIV-1 Gag protein conjugated to a TLR7/8 agonist results in the generation of HIV-1 Gag-specific Th1 and CD8+ T cell responses. J Immunol. 2005 Jun 15;174(12):7676-83.
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