Major Challenges in Providing an Effective and Timely Pandemic Vaccine for Influenza A(H7N9)

From The Journal of the American Medical Association, JAMA Network

Michael T. Osterholm, PhD, MPH; Katie S. Ballering, PhD; Nicholas S. Kelley, PhD 

JAMA. 2013;():1-2. doi:10.1001/jama.2013.6589.

Published online May 9, 2013

The emergence of avian influenza A(H7N9) virus in humans has public health authorities around the world on high alert for the potential development of a human influenza pandemic.¹ As of May 8, 2013, authorities had identified 131 confirmed cases and 32 deaths among residents of 8 provinces and 2 municipalities in China.²

Three primary scenarios exist for how this A(H7N9) virus outbreak will unfold. First, the virus could disappear in the animal reservoir, ending new human cases. Second, the virus could persist in the animal reservoir, resulting in sporadic human infections. Third, the virus could, through mutation or reassortment, become readily transmissible between humans, resulting in a global pandemic.

The arsenal of public health tools to reduce morbidity and mortality from an influenza pandemic is limited. Options include vaccines, antiviral drugs, and interventions such as respiratory protection and social distancing. According to the World Health Organization (WHO), “Influenza vaccination is the most important intervention in reducing the impact of influenza, and a key component of the WHO response and preparedness efforts for influenza of pandemic potential, including avian influenza A(H5N1), A(H9N2) and A(H7N9).”³ However, seasonal and pandemic influenza vaccines have significant limitations,⁴ including limited vaccine effectiveness, the inability to identify reliable correlates of protection, and the need to distribute large quantities of vaccine early in the pandemic course.

ESTIMATED EFFECTIVENESS OF A(H7N9) VACCINES

  Data for seasonal influenza vaccines and the 2009 A(H1N1)pdm09 vaccines provide a basis for estimatingpotential effectiveness of A(H7N9) vaccines. Inactivated seasonal influenza vaccines have a pooled efficacy estimate of 59%, primarily for younger adults.4 A paucity of evidence exists for demonstrating protection in adults aged 65 years or older, particularly with influenza A vaccines. The pooled efficacy of live-attenuated influenza vaccines (LAIVs) is 83% in children aged 6 months to 7 years, but currently available data do not support effectiveness in the population aged 8 years or older.4 The median effectiveness reported in 6 studies of adjuvanted A(H1N1)pdm09 pandemic vaccines was 72% (range, 60%-93%).4 In a study of unadjuvanted A(H1N1)pdm09 vaccine conducted in the United States, effectiveness was 56% (95% CI, 23%-75%).4 For these studies, most participants were younger than 50 years, with approximately half younger than 18 years. There is no reason to believe that a yet-to-be-developed pandemic A(H7N9) vaccine will perform any better than existing seasonal vaccines or the A(H1N1)pdm09 vaccines, particularly with regard to vaccine efficacy in persons older than 65 years. To date, the median age of H7N9 cases is 60 years. If a pandemic occurs and this epidemiologic pattern persists, a pandemic A(H7N9) vaccine, even if it includes an adjuvant, will likely have limited to modest effects on the overall morbidity and mortality from the novel strain.

DETERMINING AND MEASURING CORRELATES OF PROTECTION FOR A(H7N9) VACCINES

In the United States, vaccine dose for inactivated pandemic vaccines is determined by the amount of hemagglutinin head antigen needed to achieve a hemagglutination inhibition (HI) titer of 1:40 in at least 70% of children and adults younger than 65 years or, alternatively, the amount of antigen needed to demonstrate that 40% of recipients have a 4-fold or greater increase in HI.⁵ Even though HI titers have been used for decades as a correlate of protection for influenza vaccines, the US Food and Drug Administration (FDA) noted that “prospectively designed studies to evaluate the effectiveness of influenza vaccines have not identified a specific HI antibody titer associated with protection against culture-confirmed influenza illness.”⁵ LAIVs do not have a recognized correlate of protection, which will create challenges for interpreting immunogenicity of candidate H7N9 vaccines.

The limited data available suggest that for an H7N9 vaccine to provide protection, it will likely require significantly more antigen than seasonal vaccines, will likely require an adjuvant, or both. Two phase 1 clinical studies of an inactivated H7 vaccine have been conducted to date.^6- 7 In one study using an unadjuvanted H7N7 vaccine, only 8 of 22 recipients receiving 2 doses of 90-μg vaccines had at least a 4-fold HI increase; none achieved a 1:40 titer.⁶ In another study of an H7N1 vaccine with adjuvant, none of 13 recipients receiving 2 doses of a 24-μg adjuvanted vaccine had a 1:40 titer.⁷ A single phase 1 study of an H7N3 LAIV demonstrated safety and most participants had a measurable immune response, although a recognized correlate of protection for LAIV has not been identified.⁸ Previous studies with H5N1 vaccines required 2 90-μg doses for 50% of adults to develop 1:40 HI titers; however, an adjuvanted vaccine using 3.8 μg showed improved results.

TIMELY AVAILABILITY OF A(H7N9) VACCINES

For A(H7N9) vaccines to be beneficial during an emerging pandemic, vaccines must be made available quickly. Factors determining availability include time to develop and distribute vaccine and global manufacturing capacity. Both factors will be influenced by the minimum immunogenic antigen dosage.

Efforts are under way to develop seed strains for A(H7N9) vaccines, manufacture clinical study vaccine lots, and conduct phase 1 clinical studies. The US Department of Health and Human Services anticipates that these efforts will be completed within 5 months. However, actual vaccine manufacturing likely will not occur until an A(H7N9) pandemic is considered imminent. Since it typically takes 17 to 22 weeks from preparation of the seed strain until vaccine can be shipped, the best-case scenario is a timeframe of 4 months from placement of vaccine orders to availability of production lots for distribution. Recent federal investments in potency testing may reduce this time. Depending on when vaccines are ordered, the manufacturers' ability to convert from seasonal vaccine to pandemic vaccine production, and how quickly the pandemic spreads, it is possible that vaccines will arrive in limited quantities but after the critical point when they will significantly affect morbidity and mortality, as occurred in 1957, 1968, and 2009.⁴

The 2009 A(H1N1)pdm09 illustrates the potential challenges of vaccine availability during an A(H7N9) pandemic. In late April 2009, public health officials determined that the A(H1N1)pdm09 pandemic was under way. Within weeks, the first vaccine seed strains were made available to manufacturers. At the same time, government agencies in a number of countries placed large orders for pandemic vaccine. Phase 1 clinical studies and the early manufacturing of bulk vaccine antigen occurred in parallel. Despite these efforts, most pandemic vaccine was not available in the United States until late October, almost 2 months after the second wave peaked.⁴ This same situation occurred in 1957 and 1968; vaccine was too little, too late.

Current annual global capacity for manufacturing hemagglutinin-head influenza vaccine is approximately 4.54 billion monovalent 15-μg doses.⁹ The antigen concentration for an H7N9 vaccine is currently unknown, but if 90 μg is required, global annual manufacturing capacity will be approximately 757 million doses of monovalent influenza vaccines. This is less than 15% of the global need and much of it will not be available until 6 or more months after manufacturing begins. Adjuvants may augment vaccine capacity, but development of an adequate global vaccine supply will remain an unprecedented challenge.

REGULATORY APPROVAL PROCESS FOR A(H7N9) VACCINE

A(H7N9) pandemic vaccine, if needed in the near future, will require a different regulatory process compared with the 2009 pandemic vaccine. Because A(H7N9) influenza virus is a novel human virus strain and limited data are available for H7 strains, manufacturers will not be able to apply to the FDA for license approval of an A(H7N9) vaccine under the provisions of a “strain change” request. Rather, the FDA will likely need to review data from the planned clinical studies and determine whether to issue Emergency Use Authorizations for A(H7N9) vaccines; this would be the first such authorization for vaccines.¹⁰

TOWARD THE FUTURE

Another influenza pandemic is inevitable. Even with recent additional vaccine manufacturing capacity and improvements in potency testing, the global public health community remains woefully underprepared for an effective vaccine response to a pandemic. To be successful in meeting the challenge of a severe pandemic, the influenza vaccine enterprise must move forward with the development of novel antigen influenza vaccines that protect most individuals from multiple strains of influenza.

AUTHOR INFORMATION

Corresponding Author: Michael T. Osterholm, PhD, MPH, Center for Infectious Disease Research and Policy, University of Minnesota, 420 Delaware St, SE MMC263, Minneapolis, MN 55455 (mto@umn.edu).

Published Online: May 9, 2013. doi:10.1001/jama.2013.6589

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Funding/Support: This work has been funded in part with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under contract HHSN266200700007C.

Role of the Sponsor: The National Institute of Allergy and Infectious Diseases had no role in the preparation, review, or approval of the manuscript or in the decision to submit the manuscript for publication.

Disclaimer: The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.

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