On the NIH Grant Review Process

1000 miles

It is common knowledge amongst biomedical researchers around my age (46) that the NIH Grant Funding system has never really recovered from the Bush era triple whammy of (1) tax cuts, (2) starting a war in Iraq, and (3) starting a war in Afghanistan. I am not judging these actions, but I am simply stating that since 2004, the NIH has faced budgetary constraints which have gotten progressively worse over time. More limiting than the actual budgetary constraints is the apparent inability of the NIH leadership to make rational choices about how best to deal with their budgetary constraints. In simple terms, the NIH had two options at their disposal to deal with this issue and these were:

(1) reduce the average size of NIH awards (i.e, so that everyone feels the pain), or (2) reduce the % of investigators the NIH continues to support by throwing more than 50% of previously supported investigators to the curb.  Whether by design or by accident, the NIH has effectively chosen the latter route.

I am one of the more than 50% of formerly NIH-funded investigators whose research was deemed unworthy of NIH support either by design or by inaction. For my lab, the end result is the same….no money equals a very slow pace of research.

I would like to review the specifics of my situation, as a means to bring a personal face to what these NIH grant funding policies have done to many researchers in my general age range who are (1) well beyond the junior investigator years that the NIH continues to support (i.e., scientists under 35 = cheap labor) but who are (2) not yet eligible for social security, and thus have not risen to the rank of “senior investigators” who run the labs that are populated by cheap labor / junior investigators (i.e., graduate students and postdoctoral fellows).

I have been providing my scientific colleagues with consistent and unwavering evidence for the past 8 years that a live-attenuated HSV-2 vaccine would be a superior strategy to stop the spread of HSV-2 genital herpes relative to the NIH-supported HSV-2 vaccine approaches that keep failing (2007 – present). When I began pursuing this line of investigation, many of my reviewers pointed out that a HSV-2 vaccine was currently in the clinical trials pipeline and that this HSV-2 vaccine would be available to the public in just a few years. The HSV-2 vaccine candidate in question (between 2008 and 2010) was Glaxo Smith Kline’s Herpevac / gD-subunit vaccine, which failed in human clinical trials precisely as I had predicted in 2007 [Halford, 2007].

Eight years later, where are we? Another 100 to 150 million people have been newly infected with HSV-2, and my reviewers are now reassuring me that the latest iteration of the HSV-2 subunit vaccine concept will succeed (e.g., Agenus’s HerpV vaccine and Genocea’s GEN-003 vaccine).  My lab has published numerous papers that add specificity to what I have been saying for 8 years; a HSV-2 subunit vaccine strategy is unlikely to succeed regardless of how many more decades we spend exploring, renaming, and reinventing the same failed approach.  In contrast, a live-attenuated HSV-2 vaccine is up to 100 times more effective.

Finally, I note that the significance of NIH Grant Support is two-fold. First, a 5-year R01 grant award from the NIH may provide $750,000 to $1.25 million in direct support to a laboratory for hiring personnel and purchasing supplies; research tends to proceed at a faster pace when there is cash available to pay the bills.  Second, a 5-year R01 grant from the NIH sends a message to other scientists that the NIH believes a line of scientific investigation is important enough to merit their support.  Reciprocally, the fact that my lab has been unable to secure an R01 to fund the investigation of a live-attenuated HSV-2 vaccine sends the implicit message that there is something wrong with myself, the live HSV-2 vaccine approach, or the underlying science.

Perhaps my NIH research grants and the ideas contained therein really are that lame, and don’t deserve the time or consideration of NIH reviewers.  For the rare person who is willing to read the science and substance of these grant applications, I will leave it up to you to decide.  In this blog post, I am making public (1) every NIH grant application I have ever authored on my lab’s investigation of a live-attenuated HSV-2 vaccine, (2) the comments of NIH reviewers that I received on each of those grant applications, and (3) the publications from my laboratory that have come out on the topics of HSV-2 vaccines during the past 8 years.

Perhaps 2015 will be the year that a NIH study section will decide that it is time to try something different in the sphere of HSV-2 vaccines, and support the Halford Lab’s ongoing investigation of a live-attenuated HSV-2 vaccine.  In my estimation, this simple step would increase the odds of advancing an effective HSV-2 vaccine into clinical usage by 10- to 100-fold compared to the approaches the NIH has been supporting for the past 30 years. One can always hope, but let’s just say that I stopped holding my breath many years ago, as the peer-review system at the NIH selects for conformity, not innovation, in the space of HSV-2 vaccines.

– Bill H.

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2006

June 2006  ⇒  Halford, W.P., J. Grace, C. Weisend, M. Soboleski, D.J.J. Carr, J.W. Balliet, Y. Imai, T.P. Margolis, and B.M. Gebhardt. 2006. ICP0 antagonizes Stat 1-dependent repression of herpes simplex virus: implications for the regulation of viral latency. Virol. J. 3: 44.    Halford lab publishes first paper describing that HSV-1 ICP0‾ mutant viruses are avirulent, but elicit a highly protective immune response against wild-type HSV-1.  This is the first evidence that a live HSV-1 ICP0‾ mutant virus would be an ideal HSV-1 vaccine candidate.  [Read Paper Here]

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2007

Jan 2007  ⇒  Halford, W.P. 2007. Towards an effective genital herpes vaccine: past lessons and future prospects. Future Virology 2: 1-6.   Halford lab publishes editorial stating that the past 20 years of HSV-2 vaccine failures with glycoprotein D subunit vaccines were disappointing but predictable, and that a live HSV-2 vaccine would be a better path forward. [Read Editorial Here]

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2008

Feb 2008  ⇒  Halford lab submits a NIH grant application requesting $275,000 in direct costs to develop a new line of safe and highly effective live HSV-2 ICP0‾ mutant vaccines.  P.I. = Halford, W.P.  Development of an effective genital herpes vaccine. NIH Grant Application #1 R21 AI081072-01 [Read R21 AI 081072 Grant Here]

June 2008  ⇒  A NIH Study Section deems that R21 AI81072 lacked sufficient merit to warrant consideration / discussion by the full panel of 20 scientists on the NIH study section.  Rather, 3 NIH reviewers provided comments and arrived at the decision the grant application was not competitive for funding consideration.  [Read Reviewers’ Comments on R21 AI081072 Here]

Nov 2008  ⇒  Halford lab re-submits a revised NIH grant application (R21 AI081072-A1) requesting $275,000 in direct costs to develop a new line of safe and highly effective live HSV-2 ICP0‾ mutant vaccines.  [Read R21 AI081072-A1 Grant Here]

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2009

Feb 2009  ⇒  The revised application, R21 AI81072-A1, is deemed meritorious enough to warrant consideration / discussion by a full panel of 20 scientists on a NIH study section.  This panel of scientists assigns the grant a reasonable, but unfundable score of ‘179’ (i.e., scores between 100 and 150 were necessary at the time to have a grand funded). [Read Reviewers’ Comments on R21 AI81072-A1 Grant Here

Interestingly enough, fate intervened and made this unfundable score suddenly “fundable” because of the American Reinvestment and Recovery Act, which made all grants below a score of 180 (i.e., 100 – 179) fundable.  Better to be lucky than smart, and luck certainly was the deciding factor on this grant.  This grant, R21 AI81072 was the one and only grant the NIH ever awarded (by accident) to my laboratory for the purpose of supporting the development of a live-attenuated HSV-2 vaccine.

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2010

March 2010  ⇒  U.S. Patent filed on HSV-1 and HSV-2 ICP0‾ mutant vaccine concept.  Davido, D. and W.P. Halford, Issued August 12, 2014, “Herpes simplex virus mutant ICP0.” U.S. Patent Number 8,802,109. This is a patent for the concept that ICP0‾ mutants of any alpha-herpesvirus (HSV-1, HSV-2, VZV, equine herpesvirus, etc) would be avirulent and could be used as an effective live vaccine.   [Read Patent]

August 2010  ⇒  Halford, W.P., R. Püschel, and B. Rakowski. 2010. Herpes simplex virus 2 ICP0mutants are avirulent and immunogenic: implications for a genital herpes vaccine. PLoS ONE 5: e12251.   As promised in Specific Aim 1 of the grant, the Halford lab publishes first paper describing that HSV-2 ICP0‾ mutant viruses are interferon-sensitive, avirulent, but elicit a highly protective immune response against wild-type HSV-2.  This is the first evidence that a live HSV-2 ICP0‾ mutant virus would be an ideal HSV-2 vaccine candidate.  [Read Paper Here]

Oct 2010  ⇒  Halford lab submits a new NIH grant application (R01 AI095328) requesting 5 years of support to develop a new line of safe and highly effective live HSV-2 ICP0‾ mutant vaccines, as by the time funding begins on this grant the 2-year R21 grant will have lapsed and the Halford Lab will be without NIH funding.  P.I. = Halford, W.P.  A safe and effective live-attenuated HSV-2 vaccine. NIH Grant Application #1 R01 AI095328-01 [Read R01 AI095328 Grant Here]

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2011

March 2011  ⇒  Halford W.P., Püschel R., Gershburg E., Wilber A., Gershburg S., Rakowski B. 2011. A live-attenuated HSV-2 ICP0‾ virus elicits 10 to 100 times greater protection against genital herpes than a glycoprotein D subunit vaccine. PLoS ONE 6:e17748.   As promised in Specific Aims 2 and 3 of the grant, the Halford lab publishes paper describing that HSV-2 ICP0‾ mutant viruses are up to 100 times more effective as a HSV-2 vaccine than the HSV-2 glycoprotein D subunit vaccines that the NIH has supported through six human clinical trials, all of which failed in the final analysis.  [Read Paper Here]

March 2011  ⇒  A NIH Study Section deems that R01 AI095328 lacked sufficient merit to warrant consideration / discussion by the full panel of 20 scientists on the NIH study section.  Rather, 2 NIH reviewers provided comments and arrived at the decision the grant application was not competitive for funding consideration.  [Read Reviewers’ Comments on R01 AI095328 Here]

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2012

June 2012  ⇒  Halford lab submits a new NIH grant application (R01 AI104935) requesting 5 years of support to develop a new line of safe and highly effective live HSV-2 ICP0‾ mutant vaccines, as a 2-year R21 grant to support this investigation has expired.  P.I. = Halford, W.P.  Comparative Analysis of HSV-2 Vaccines. NIH Grant Application #1 R01 AI104935-01  [Read R01 AI104935 Grant Here]

November 2012  ⇒  A NIH Study Section deems that R01 AI104935 lacked sufficient merit to warrant consideration / discussion by the full panel of 20 scientists on the NIH study section.  Rather, 3 NIH reviewers provided comments and arrived at the decision the grant application was not competitive for funding consideration.  [Read Reviewers’ Comments on R01 AI104935 Here]

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2013

Feb 2013  ⇒  Halford lab submits a new NIH grant application (R01 AI108635) requesting 5 years of support to develop a new line of safe and highly effective live HSV-2 ICP0‾ mutant vaccines.  P.I. = Halford, W.P.  Mechanism of Action of an Effective HSV-2 Vaccine. NIH Grant Application #1 R01 AI108635-01  [Read R01 AI108635 Grant Here]

June 2013  ⇒  Halford, W.P., J. Geltz, and E. Gershburg. 2013. Pan-HSV-2 IgG antibody in vaccinated mice and guinea pigs correlates with protection against herpes simplex virus 2. PLoS ONE. 8:e65523   After spending 12 months wrangling with reviewers who objected to the contents of this publication (first submitted in June 2012), the Halford lab was finally allowed to publish that HSV-2-specific antibodies provide a robust correlate of immunity for HSV-2 vaccines.  A competing group published a similar conclusion 5 months later in the New England Journal of Medicine.  [Read Paper Here]

July 2013  ⇒  A NIH Study Section deems that R01 AI108635 lacked sufficient merit to warrant consideration / discussion by the full panel of 20 scientists on the NIH study section.  Rather, 3 NIH reviewers provided comments and arrived at the decision the grant application was not competitive for funding consideration.  [Read Reviewers’ Comments on R01 AI108635 Here]

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2014

June 2014  ⇒  Halford, W.P. 2014. Antigenic breadth: a missing ingredient in HSV-2 subunit vaccines? Expert Rev Vaccines 13: 691–710.  The Halford Lab offers a straightforward review of (1) what has gone wrong with past HSV-2 vaccines and (2) what we might do differently in the future to obtain a HSV-2 vaccine that actually prevents gential herpes.  [Read Paper Here]

Oct 2014  ⇒  Halford lab submits a new NIH grant application.  P.I. = Halford, W.P.  Essential Role of B- and T-cell Cooperation in Vaccine-Induced Protection Against HSV-2.  NIH Grant Application #1 R01 AI119034-01 [Read R01 AI119034 Grant Here]

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2015

Feb 2015  ⇒   Geltz, J., E. Gershburg, and W.P. Halford. 2015. Herpes simplex virus 2 (HSV-2) infected cell proteins are among the most dominant antigens of a live-attenuated HSV-2 vaccine. PLoS ONE.  10(2): e0116091.   The Halford Lab offers  evidence that part of the superior efficacy of a live-attenuated HSV-2 vaccine is that a live HSV-2 vaccine elicits a B-cell / antibody response against 9 to 19 different HSV-2 proteins.  Presumably the live HSV-2 vaccine elicits a response of similar complexity in the T-cell compartment of the adaptive immune response.  [Read Paper Here]

March 2015  ⇒  A NIH Study Section deems that R01 AI119034 lacked sufficient merit to warrant consideration / discussion by the full panel of 20 scientists on the NIH study section.  Rather, 3 NIH reviewers provided comments and arrived at the decision the grant application was not competitive for funding consideration.  [Read Reviewers’ Comments on R01 AI119034 Here]

Forthcoming manuscript from my Sabbatical at the Rocky Mountain Laboratories in Spring 2014.  I am currently writing this manuscript.  ⇒   Halford, W.P., J. Geltz, R.J. Messer, and K.J. Hasenkrug.  Complete HSV-2 0ΔNLS vaccine-induced protection against genital herpes is dependent on a ‘live’ virus and host B-cells.