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VIEWPOINTONLINE FIRSTMajor Challenges in Providing an Effective andTimely Pandemic Vaccine for Influenza A(H7N9)Michael T....
adjuvanted vaccine had a 1:40 titer.7A single phase 1 study ofanH7N3LAIVdemonstratedsafetyandmostparticipantshadameasurabl...
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Major challenges in providing an effective and timely pandemic vaccine for influenza A(H7N9)

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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. In a statement The World Health Organization (WHO) described the importance of a vaccination strategy:

“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).”

Data for seasonal influenza vaccines and the 2009 A(H1N1)pdm09 vaccines provide a basis for estimating potential effectiveness of A(H7N9) vaccines. Inactivated seasonal influenza vaccines have a pooled efficacy estimate of 59%, primarily for younger adults. A paucity of evidence exists for demonstrating protection in adults aged 65 years or older, particularly with influenza A vaccines.

Three primary scenarios exist for how this A(H7N9) virus outbreak will unfold:

1. The virus could disappear in the animal reservoir, ending new human cases
2. The virus could persist in the animal reservoir, resulting in sporadic human infections.
3. The virus could, through mutation or reassortment, become readily transmissible between humans, resulting in a global pandemic.

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Major challenges in providing an effective and timely pandemic vaccine for influenza A(H7N9)

  1. 1. VIEWPOINTONLINE FIRSTMajor Challenges in Providing an Effective andTimely Pandemic Vaccine for Influenza A(H7N9)Michael T. Osterholm, PhD, MPHKatie S. Ballering, PhDNicholas S. Kelley, PhDTHE EMERGENCE OF AVIAN INFLUENZA A(H7N9) VI-rus in humans has public health authorities aroundthe world on high alert for the potential develop-ment of a human influenza pandemic.1As of May8, 2013, authorities had identified 131 confirmed cases and32 deaths among residents of 8 provinces and 2 munici-palities in China.2Three primary scenarios exist for how this A(H7N9) vi-rus outbreak will unfold. First, the virus could disappearin the animal reservoir, ending new human cases. Second,the virus could persist in the animal reservoir, resulting insporadic human infections. Third, the virus could, throughmutation or reassortment, become readily transmissible be-tween humans, resulting in a global pandemic.The arsenal of public health tools to reduce morbidity andmortality from an influenza pandemic is limited. Optionsinclude vaccines, antiviral drugs, and interventions such asrespiratory protection and social distancing. According tothe World Health Organization (WHO), “Influenza vacci-nation is the most important intervention in reducing theimpact of influenza, and a key component of the WHO re-sponse and preparedness efforts for influenza of pandemicpotential, including avian influenza A(H5N1), A(H9N2) andA(H7N9).”3However, seasonal and pandemic influenza vac-cines have significant limitations,4including limited vac-cine effectiveness, the inability to identify reliable corre-lates of protection, and the need to distribute large quantitiesof vaccine early in the pandemic course.Estimated Effectiveness of A(H7N9) VaccinesData for seasonal influenza vaccines and the 2009A(H1N1)pdm09 vaccines provide a basis for estimating po-tentialeffectivenessofA(H7N9)vaccines.Inactivatedseasonalinfluenza vaccines have a pooled efficacy estimate of 59%,primarily for younger adults.4A paucity of evidence exists fordemonstratingprotectioninadultsaged65yearsorolder,par-ticularlywithinfluenzaAvaccines.Thepooledefficacyoflive-attenuatedinfluenzavaccines(LAIVs)is83%inchildrenaged6 months to 7 years, but currently available data do not sup-port effectiveness in the population aged 8 years or older.4The median effectiveness reported in 6 studies of adju-vanted A(H1N1)pdm09 pandemic vaccines was 72% (range,60%-93%).4In a study of unadjuvanted A(H1N1)pdm09 vac-cine conducted in the United States, effectiveness was 56%(95% CI, 23%-75%).4For these studies, most participantswere younger than 50 years, with approximately half youngerthan 18 years.There is no reason to believe that a yet-to-be-developedpandemic A(H7N9) vaccine will perform any better than ex-isting seasonal vaccines or the A(H1N1)pdm09 vaccines, par-ticularly with regard to vaccine efficacy in persons older than65 years. To date, the median age of H7N9 cases is 60 years.If a pandemic occurs and this epidemiologic pattern per-sists, a pandemic A(H7N9) vaccine, even if it includes anadjuvant, will likely have limited to modest effects on theoverall morbidity and mortality from the novel strain.Determining and Measuring Correlatesof Protection for A(H7N9) VaccinesIn the United States, vaccine dose for inactivated pandemicvaccines is determined by the amount of hemagglutinin headantigen needed to achieve a hemagglutination inhibition (HI)titer of 1:40 in at least 70% of children and adults youngerthan 65 years or, alternatively, the amount of antigen neededto demonstrate that 40% of recipients have a 4-fold or greaterincrease in HI.5Even though HI titers have been used for de-cades as a correlate of protection for influenza vaccines, theUS Food and Drug Administration (FDA) noted that “pro-spectively designed studies to evaluate the effectiveness of in-fluenza vaccines have not identified a specific HI antibodytiter associated with protection against culture-confirmed in-fluenza illness.”5LAIVs do not have a recognized correlateof protection, which will create challenges for interpretingimmunogenicity of candidate H7N9 vaccines.ThelimiteddataavailablesuggestthatforanH7N9vaccineto provide protection, it will likely require significantly moreantigenthanseasonalvaccines,willlikelyrequireanadjuvant,orboth.Twophase1clinicalstudiesofaninactivatedH7vac-cinehavebeenconductedtodate.6,7Inonestudyusinganun-adjuvanted H7N7 vaccine, only 8 of 22 recipients receiving 2doses of 90-␮g vaccines had at least a 4-fold HI increase; noneachieveda1:40titer.6InanotherstudyofanH7N1vaccinewithadjuvant, none of 13 recipients receiving 2 doses of a 24-␮gAuthor Affiliations: Center for Infectious Disease Research and Policy (Drs Os-terholm, Ballering, and Kelley), Minnesota Center of Excellence for InfluenzaResearch and Surveillance (Drs Osterholm and Kelley), University of Minnesota,Minneapolis.Corresponding Author: Michael T. Osterholm, PhD, MPH, Center for InfectiousDisease Research and Policy, University of Minnesota, 420 Delaware St, SE MMC263,Minneapolis, MN 55455 (mto@umn.edu).©2013 American Medical Association. All rights reserved. JAMA, Published online May 9, 2013 E1Downloaded From: http://jama.jamanetwork.com/ on 05/20/2013
  2. 2. adjuvanted vaccine had a 1:40 titer.7A single phase 1 study ofanH7N3LAIVdemonstratedsafetyandmostparticipantshadameasurableimmuneresponse,althougharecognizedcorre-late of protection for LAIV has not been identified.8Previousstudies with H5N1 vaccines required 2 90-␮g doses for 50%ofadultstodevelop1:40HItiters;however,anadjuvantedvac-cine using 3.8 ␮g showed improved results.Timely Availability of A(H7N9) VaccinesForA(H7N9)vaccinestobebeneficialduringanemergingpan-demic, vaccines must be made available quickly. Factors de-termining availability include time to develop and distributevaccine and global manufacturing capacity. Both factors willbeinfluencedbytheminimumimmunogenicantigendosage.Efforts are under way to develop seed strains for A(H7N9)vaccines,manufactureclinicalstudyvaccinelots,andconductphase1clinicalstudies.TheUSDepartmentofHealthandHu-man Services anticipates that these efforts will be completedwithin5months.However,actualvaccinemanufacturinglikelywill not occur until an A(H7N9) pandemic is considered im-minent. Since it typically takes 17 to 22 weeks from prepara-tionoftheseedstrainuntilvaccinecanbeshipped,thebest-casescenarioisatimeframeof4monthsfromplacementofvaccineorderstoavailabilityofproductionlotsfordistribution.Recentfederal investments in potency testing may reduce this time.Dependingonwhenvaccinesareordered,themanufacturers’ability to convert from seasonal vaccine to pandemic vaccineproduction, and how quickly the pandemic spreads, it is pos-siblethatvaccineswillarriveinlimitedquantitiesbutafterthecriticalpointwhentheywillsignificantlyaffectmorbidityandmortality, as occurred in 1957, 1968, and 2009.4The 2009 A(H1N1)pdm09 illustrates the potential chal-lenges of vaccine availability during an A(H7N9) pan-demic. In late April 2009, public health officials deter-mined that the A(H1N1)pdm09 pandemic was under way.Within weeks, the first vaccine seed strains were made avail-able to manufacturers. At the same time, government agen-cies in a number of countries placed large orders for pan-demic vaccine. Phase 1 clinical studies and the earlymanufacturing of bulk vaccine antigen occurred in paral-lel. Despite these efforts, most pandemic vaccine was notavailable in the United States until late October, almost 2months after the second wave peaked.4This same situationoccurred in 1957 and 1968; vaccine was too little, too late.Current annual global capacity for manufacturing hema-gglutinin-headinfluenzavaccineisapproximately4.54billionmonovalent 15-␮g doses.9The antigen concentration for anH7N9 vaccine is currently unknown, but if 90 ␮g is required,global annual manufacturing capacity will be approximately757milliondosesofmonovalentinfluenzavaccines.Thisislessthan15%oftheglobalneedandmuchofitwillnotbeavailableuntil6ormoremonthsaftermanufacturingbegins.Adjuvantsmayaugmentvaccinecapacity,butdevelopmentofanadequateglobalvaccinesupplywillremainanunprecedentedchallenge.Regulatory Approval Process for A(H7N9) VaccineA(H7N9) pandemic vaccine, if needed in the near future,will require a different regulatory process compared withthe 2009 pandemic vaccine. Because A(H7N9) influenza vi-rus is a novel human virus strain and limited data are avail-able for H7 strains, manufacturers will not be able to applyto the FDA for license approval of an A(H7N9) vaccine un-der the provisions of a “strain change” request. Rather, theFDA will likely need to review data from the planned clini-cal studies and determine whether to issue Emergency UseAuthorizations for A(H7N9) vaccines; this would be the firstsuch authorization for vaccines.10Toward the FutureAnother influenza pandemic is inevitable. Even with re-cent additional vaccine manufacturing capacity and im-provements in potency testing, the global public health com-munity remains woefully underprepared for an effectivevaccine response to a pandemic. To be successful in meet-ing the challenge of a severe pandemic, the influenza vac-cine enterprise must move forward with the developmentof novel antigen influenza vaccines that protect most indi-viduals from multiple strains of influenza.Published Online: May 9, 2013. doi:10.1001/jama.2013.6589Conflict of Interest Disclosures: All authors have completed and submitted the ICMJEForm for Disclosure of Potential Conflicts of Interest and none were reported.Funding/Support: This work has been funded in part with federal funds from theNational 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 hadno role in the preparation, review, or approval of the manuscript or in the decisionto submit the manuscript for publication.Disclaimer: The contents of this article are solely the responsibility of the authorsand do not necessarily represent the official views of the National Institutes of Health.REFERENCES1. Emergence of Avian Influenza A(H7N9) Virus Causing Severe Human Illness—ϪChina, February-April 2013. MMWR. http://www.cdc.gov/mmwr/pdf/wk/mm62e0501.pdf. Accessed May 8, 2013.2. Schnirring L. Another death in China raises H7N9 fatalities to 32. CIDRAP NEWS.May 8, 2013. http://www.cidrap.umn.edu/cidrap/content/influenza/avianflu/news/may0813china.html. Accessed May 9, 2013.3. World Health Organization. Vaccine response to the avian influenza A(H7N9)outbreak. May 2013. http://www.who.int/influenza/vaccines/virus/CandidateVaccineVirusesH7N9_02May13.pdf. Accessed May 9, 2013.4. Osterholm MT, Kelley NS, Manske JM, et al. The compelling need for game-changing influenza vaccines: an analysis of the influenza vaccine enterprise andrecommendations for the future. CIDRAP. Oct 2012. http://www.cidrap.umn.edu/cidrap/center/mission/articles/ccivi-landing.html. Accessed May 8, 2013.5. US Food and Drug Administration. Guidance for industry: clinical data neededto support licensure of pandemic influenza vaccines. May 2007. http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/ucm074786.htm. Accessed May 8, 2013.6. Couch RB, Patel SM, Wade-Bowers CL, Nin˜o D. A randomized clinical trial ofan inactivated avian influenza A (H7N7) vaccine. PLoS One. 2012;7(12):e49704.7. Cox RJ, Madhun AS, Hauge S, et al. A phase I clinical trial of a PER.C6 cell growninfluenza H7 virus vaccine. Vaccine. 2009;27(13):1889-1897.8. Talaat KR, Karron RA, Callahan KA, et al. A live attenuated H7N3 influenzavirus vaccine is well tolerated and immunogenic in a phase I trial in healthy adults.Vaccine. 2009;27(28):3744-3753.9. Partridge J, Kieny MP. Global production capacity of seasonal influenza vac-cine in 2011. Vaccine. 2013;31(5):728-731.10. Pandemic and All-Hazards Preparedness Reauthorization Act, Pub L No. 113-5,§564 (b)(1)(C). http://www.govtrack.us/congress/bills/113/hr307.VIEWPOINTE2 JAMA, Published online May 9, 2013 ©2013 American Medical Association. All rights reserved.Downloaded From: http://jama.jamanetwork.com/ on 05/20/2013

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