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Man Versus Flu: The Search for a Universal Vaccine Let me tell you the secret that has led me to my goal: My strength lies solely in my tenacity. — Louis Pasteur

by KEITH BERMAN, MPH, MBA

NO ONE CAN argue that there are not plenty of options these days for annual immunization against the flu. For the 2013-14 season, seven manu - facturers — up from four a decade ago — are offering a smorgasbord of inactivated and live-attenuated and recombinant, trivalent and quadriva - lent, standard and high-dose, and intramuscular and intranasal and intradermal flu vaccines. Yet despite the panoply of choices, influenza remains a serious public health threat. The most recent 2012-13 flu season presents a sobering reminder of the limits of our current vaccine technology. While flu vaccines were 56 percent effective for all recipients, they were just 9 percent effective for persons age 65 and older. The number of flu- related pediatric deaths during last year’s flu season was the highest reported since data collection began in 2004. 1 The hospitalizations avoided and lives saved by current-generation flu vaccines unquestionably justify the annual effort and cost of hunting down target strains, then manufacturing and administering around 135 million vac - cine doses this season. 2 But this winter, tens of millions of Americans will come

48 BioSupply Trends Quarterly • October 2013 INDUSTRY INSIGHT

down with the flu (including many, of systems can “remem ber” and generate As a growing portion of the flu- course, who neglect to get their annual neutralizing to similar- infected — or vaccinated — population flu shot), millions of workdays will be look ing flu strains has bolstered builds effective neutralizing antibodies lost, as many as 200,000 or more people enthu siasm about the prospects for a against the prevalent influenza virus may be hospitalized, and thousands will universal vaccine or vac cine cocktail. strains, natural selection favors new die from flu-related complications. variants that are capable of escaping The obvious need remains for “a Influenza Viruses as Escape Artists host immunity by virtue of their altered vaccine that you don’t have to give Despite their different production HA protein structure. Thus, we see every year that works better,” said Dr. processes, presentations and delivery of the flu viruses that circulate over the course of each season. The greater the mismatch between the drifted virus strains and the early Influenza viruses exploit three potent virulent strains against which the season’s flu vaccine was manufactured, evolutionary strategies that enable them the more the efficacy of the vaccine is diminished. to return to infect us again and again. Periodic flu pandemics occur when entirely new influenza virus subtypes are created by genetic reassortment Joseph Bresee, a senior epidemiologist options, all licensed influenza vaccines when two different viruses co-infect the in Centers for Disease Control and work by inducing protective humoral host cell. Unlike most viruses that have Prevention’s (CDC’s) Influenza Division. 3 immunity against antigenic targets on a single RNA strand, the flu virus “Among the two dozen vaccine-pre - the globular “head” portion of hemag - includes eight RNA strands to encode ventable diseases, including measles, glutinin (HA), a surface its genome. When all those strands mumps, polio, smallpox and hepatitis, that the virus uses to attach itself to intermix, a novel “reassortant” progeny seasonal influenza is the only one for res piratory tract and other host cells virus can be created that never existed which a new vaccine is recommended (Figure 1). When exposed to the circu - before. The H1N1 strain that caused the every year. A more efficient approach is lating live flu virus, the immunized , for example, long overdue,” noted Dr. Anthony individual rapidly produces specific was a complex reassortant of avian, Fauci, director of the National Institute antibodies that inhibit virus infection of Allergy and Infectious Diseases. 4 by blocking HA attachment to our cells. Possibly the best evidence for the Yet, when the next flu season rolls fea sibility of a longer-acting, broadly around, without immunization Figure 1. Stucture of the Hemagglutinin protective “universal” flu vaccine comes against the new epidemic strain, we are (HA) Protein from a natural experiment — the once again susceptible to contracting sur prisingly mild 2009 H1NI flu the illness. pan demic. Antigenically distinct from Influenza viruses exploit three potent recently circulating H1N1 seasonal flu evolutionary strategies that enable them viruses, that H1N1 virus turned out to to return to infect us again and again. be a distant relative of the virus The error-prone replication of viral respon sible for the devastating 1918 RNA strands in the human or other Spanish flu pandemic. A new analysis by mammalian host cell generates sponta - scientists at the Wistar Institute has neous mutations that translate into revealed that people of different ages changes focused in particular in the experienced vastly different polymorphic head portion of the viral response rates to the 2009 H1N1 HA surface protein. pan demic virus, depending on whether occurs when significant mutations they were exposed to a seasonal H1N1 create new flu viruses that are poorly virus many decades earlier. 5 This new recognized by large seg ments of the understand ing that our immune population.

BioSupply Trends Quarterly • October 2013 49 BioFocus INDUSTRY INSIGHT

Figure 2. Influenza Virus: Potential Target Antigens for a Universal Vaccine rate one or more of the following three viral proteins: • Hemagglutinin A (HA) stem region. Also referred as the HA stalk, this region of the HA glycoprotein is highly con - served. One group has designed a novel vaccine that includes the stem portion of HA without the globular head; mice vaccinated with this “headless HA” were completely protected against a lethal influenza virus challenge. 7 Separately, researchers at the Scripps Research Institute report isolating a (MAb) that rec - ognizes a highly conserved epitope on the stem region of HA and neutralized influenza virus by preventing virus-host membrane fusion. 8 They and others have subsequently identified other MAbs that target the HA stem region, creating an entirely separate theoretical opportunity to produce a MAb cocktail that could be used to provide passive immunity in cases of severe influenza. 9 • Matrix protein 2 (M2e). This highly conserved external domain of this human and swine influenza viruses Universal Flu Vaccine Candidates influenza A surface glycoprotein plays a that further reassorted with a The functional premise of most key role in virus morphogenesis and Eurasian swine flu virus. 6 But as a development-stage universal influenza assembly. On hopes that it can induce growing share of the population was A and B vaccines is simple: Induce highly cross-protection against different sub - exposed to it, immune selection resulted in antigenic drift of the 2009 H1N1 virus, resulting in its transition to a seasonal flu virus. By the end of the last decade, Thus, the flu virus rebounds to create new epidemics each year by continu - cautious optimism was being expressed ally changing its antigenic presenta - tion, which both necessitates the annual at research conferences that the first licensure and production of new vac - cines, and leaves us highly vulnerable to the next flu pandemic. But encour - universal vaccine could be available aging recent findings reported by some laboratories have raised hopes in as little as five years. that a long-dreamed-about strategy of targeting highly conserved viral proteins could yield broadly protec - cross-reactive antibodies against highly types, M2e has been selected for a number tive “universal” vaccines that confer conserved antigenic targets across dif - of universal influenza A vaccine candi - long-term protection against both ferent influenza virus subtypes and dates. To improve its immunogenicity, drifted and pandemic influenza A strains (Figure 2). Most promising several groups have linked M2e to such and B. development-stage vaccines incorpo - platforms as hepatitis B virus core,

50 BioSupply Trends Quarterly • October 2013 S

SHE KEEPS YOUR PRESCRIPTIONS UP-TO-DATE THIS FLU SEASON, ASK YOUR SHE ANSWERS PHARMACIST YOUR HEALTH ABOUT FLUCELVAX QUESTIONS (INFLUENZA VIRUS (WITH A SMILE) VACCINE)

SHE EVEN GIVES YOU YOUR FLU SHOT EVERY YEAR

FLUCELVAX (Infl uenza Virus Vaccine) was the fi rst FDA-approved cell-based fl u vaccine made with an advanced scientifi c process. It does not contain antibiotics. And it doesn’t contain preservatives. FLUCELVAX is for people 18 years or older.

To fi nd out where to get your FLUCELVAX shot, go to FLUCELVAX.com.

What is FLUCELVAX® (Infl uenza Virus Vaccine)? What are the most common side effects FLUCELVAX (Infl uenza Virus Vaccine) is a vaccine that of FLUCELVAX (Infl uenza Virus Vaccine)? helps protect against infl uenza (fl u). • pain or redness where you got the shot FLUCELVAX is for people aged 18 and older. Vaccination • headache with FLUCELVAX may not protect all people who receive • tiredness the vaccine. • muscle aches • feeling unwell (malaise) Important Safety Information for FLUCELVAX These are not all of the possible side effects of Who should not get FLUCELVAX? FLUCELVAX. You can ask your healthcare provider for • You should not get FLUCELVAX if you have had a severe a complete list of possible side effects. allergic reaction to any of the ingredients in the vaccine Ask your healthcare provider for advice about any side Who may not be able to get FLUCELVAX? effects that concern you. You may report side effects to Tell your healthcare provider if you: the Vaccine Adverse Events Reporting System (VAERS) by • have ever had Guillain-Barré Syndrome (severe calling 1-800-822-7967 or by going to http://vaers.hhs.gov. muscle weakness) after getting a fl u shot • have an allergy to rubber latex To report SUSPECTED ADVERSE REACTIONS, contact Novartis Vaccines at 1-877-683-4732 or VAERS at What if I have a weakened immune system? 1-800-822-7967 and www.vaers.hhs.gov. Tell your healthcare provider if you have problems with your immune system, as your immune response to the vaccine may be less.

Please see brief summary of Prescribing Information for FLUCELVAX on adjoining pages.

Novartis Vaccines and Diagnostics, Inc. RETHINK FLU. East Hanover, New Jersey 07936-1080 © 2013 Novartis Vaccines and Diagnostics, Inc. August 2013 149531

FLUCELVAX (Influenza Virus Vaccine) Table 1: Solicited Adverse Reactions in the Safety Population Reported Suspension for Intramuscular Injection Within 7 Days of Vaccination in Study 1* 2013-2014 Formula Adults 18 through 49 Years Initial U.S. Approval: 2012 Percentages (%) BRIEF SUMMARY: See package insert for full prescribing information. 1 INDICATIONS AND USAGE FLUCELVAX Placebo FLUCELVAX® is an inactivated vaccine indicated for active immunization for N=3813 N=3894 the prevention of influenza disease caused by influenza virus subtypes A Local adverse reactions and type B contained in the vaccine Injection site pain 30 10 FLUCELVAX is approved for use in persons 18 years of age and older. Erythema 13 10 4 CONTRAINDICATIONS Induration 6 3 Do not administer FLUCELVAX to anyone with a history of severe allergic reaction (e.g. anaphylaxis) to any component of the vaccine [see Swelling 6 3 Description (11) in the full prescribing information]. Ecchymosis 4 4 5 WARNINGS AND PRECAUTIONS Systemic adverse reactions 5.1 Guillain-Barré Syndrome Headache 15 15 The 1976 swine was associated with an elevated risk of Guillain-Barré syndrome (GBS). Evidence for a causal relation of GBS Fatigue 10 10 with other influenza vaccines is inconclusive; if an excess risk exists, it Myalgia 12 7 is probably slightly more than 1 additional case per 1 million persons Malaise 8 6 vaccinated. If GBS has occurred within 6 weeks of receipt of a prior influenza vaccine, the decision to give FLUCELVAX should be based on Chills 6 6 careful consideration of the potential benefits and risks. Arthralgia 3 3 5.2 Latex Sweating 3 3 The tip caps of the pre-filled syringes may contain natural rubber latex Fever (≥38°C) 1<1 which may cause allergic reactions in latex-sensitive individuals. [see Description (11) in the full prescribing information] * NCT00630331 5.3 Preventing and Managing Allergic Reactions Study 2 was a randomized, double-blind study comparing FLUCELVAX Appropriate medical treatment and supervision must be available to (N=1330) to a U.S. licensed comparator (N=1324) in adults 18 years of age manage possible anaphylactic reactions following administration of the or older. The mean age was 43.7 years of age for adults 18 to 64 years of vaccine. age and 71.3 years of age for adults 65 years of age and older; 57% of subjects were female and 100% were Caucasian. The safety data observed 5.4 Altered Immunocompetence are summarized in Table 2. After vaccination with FLUCELVAX, immunocompromised individuals, including those receiving immunosuppressive therapy, may have a reduced Table 2: Solicited Adverse Reactions in the Safety Population Reported immune response. [See Concurrent use with Immunosuppresive Therapies Within 7 Days of Vaccination in Study 2* (7.2)] Adults 18 through 64 Years Adults 65 Years of Age 5.5 Limitations of Vaccine Effectiveness and Older Vaccination with FLUCELVAX may not protect all vaccine recipients against Percentages (%) influenza disease. FLUCELVAX Comparator** FLUCELVAX Comparator** 6 ADVERSE REACTIONS N=821 N=841 N=509 N=483 Overall, the most common (≥10 %) solicited adverse reactions occurring in Local adverse adults 18 to 64 years of age within 7 days of vaccination with FLUCELVAX reactions were pain at the injection site (28%), erythema at the injection site (13%), Injection site headache (16%), fatigue (12%), myalgia (11%) and malaise (10%). The pain 20 15 8 4 most common ( 10%) solicited adverse reactions occurring in adults ≥ Erythema 14 15 10 11 65 years of age and older within 7 days of vaccination were erythema at the injection site (10%), fatigue (11%), headache (10%) and malaise (10%). Induration 6 6 5 4 6.1 Clinical Trials Experience Swelling 4 4 4 2 Because clinical studies are conducted under widely varying conditions, Ecchymosis 3 3 4 4 adverse reaction rates observed in the clinical studies of a vaccine cannot Systemic be directly compared to rates in clinical studies of another vaccine, and may adverse not reflect rates observed in clinical practice. reactions The safety of FLUCELVAX was evaluated in seven randomized, controlled Headache 12 11 10 11 studies conducted in the US, Europe and New Zealand. The safety Fatigue 11 11 11 13 population includes 5709 adults 18 through 64 years of age and 572 adults Myalgia 7 8 6 8 65 years of age and older. Malaise 11 11 10 11 In all studies, solicited local injection site and systemic adverse reactions Chills 4 4 3 4 were collected from subjects who completed a symptom diary card for 7 days following vaccination. Arthralgia 5 5 6 7 One of the 7 clinical trials was a randomized, double-blind, placebo- Sweating 5 4 7 8 controlled study that evaluated a total of 11376 subjects: FLUCELVAX Fever (≥38° C) 1 1 <1 1 (N=3813), placebo (N=3894) and another influenza vaccine. The population * NCT00492063 was 18 through 49 years of age (mean 32.8 years), 55% were female and **AGRIFLU 84% were Caucasian. The safety data observed for FLUCELVAX and placebo Unsolicited adverse events, including serious adverse events (SAEs), were are summarized in Table 1. collected for 21 days after vaccination in five studies. In adults 18 through 64 years of age (N=4038), 13% (284 out of 2266) of subjects who received FLUCELVAX and 13% (224 out of 1772) of subjects who received a U.S. licensed comparator vaccine reported at least one unsolicited adverse event within 21 days after vaccination. The most commonly reported unsolicited adverse events after FLUCELVAX vaccination were rhinitis (3%), headache (2%) and oropharyngeal pain (2%). In adults 65 years of age and older (N=2013), 11% (110 out of 997) of subjects who received FLUCELVAX and 9% (95 out of 1016) of subjects who received a U.S. licensed comparator vaccine reported at least one unsolicited adverse event within 21 days after vaccination. Within this age group, the most commonly reported

unsolicited adverse events after FLUCELVAX vaccination were rhinitis (3%) In a reproductive and developmental toxicity study, the effect of FLUCELVAX and cough (2%). In both age groups, all other unsolicited adverse events on embryo-fetal and post-natal development was evaluated in pregnant were reported in 1% or less of subjects. rabbits. Animals were administered FLUCELVAX by intramuscular injection In the seven controlled studies of FLUCELVAX, the rates of serious adverse 3 times prior to gestation, during the period of organogenesis (gestation events were collected for 21 days in two studies and for 6 to 9 months in day 7) and later in pregnancy (gestation day 20), 0.5 mL/rabbit/occasion five studies. The rates (in all seven controlled studies) of serious adverse (approximately 15-fold excess relative to the projected human dose on events among adults 18 through 64 years of age were 1% (84 out of 6388) a body weight basis). No adverse effects on mating, female fertility, in groups that received FLUCELVAX, 1% (55 out of 5745) in groups that pregnancy, embryo-fetal development, or post-natal development were received US licensed comparator vaccines and 1% (37 out of 3894) in observed. There were no vaccine-related fetal malformations or other groups that received placebo. The rates of serious adverse events among evidence of teratogenesis. adults 65 years of age and older were 4% (36 out of 997) in groups that 8.3 Nursing Mothers received FLUCELVAX and 4% (44 out of 1016) in groups that received a US FLUCELVAX has not been evaluated in nursing mothers. It is not known licensed comparator vaccine. whether FLUCELVAX is excreted in human milk. Because many drugs are 6.2 Postmarketing Experience excreted in human milk, caution should be exercised when FLUCELVAX is There are no available postmarketing safety data with FLUCELVAX. administered to a nursing woman. 7 DRUG INTERACTIONS 8.4 Pediatric Use 7.1 Concomitant use with Other Vaccines Safety and effectiveness have not been established in children less than No data are available to assess the concomitant administration of 18 years of age. FLUCELVAX with other vaccines. 8.5 Geriatric Use If FLUCELVAX is to be given at the same time as another injectable Of the total number of subjects who received one dose of FLUCELVAX in vaccine(s), the vaccine(s) should always be administered at different clinical studies (6711), 9% (572) were 65 years of age and older and 2% injection sites. Do not mix FLUCELVAX with any other vaccine in the same (140) were 75 years or older. syringe or vial. The majority of local and general adverse events were reported less 7.2 Concurrent use with Immunosuppressive Therapies frequently in adults 65 years of age and older as compared to adults Immunosuppressive therapies, including irradiation, antimetabolites, <65 years of age. [See Adverse Reactions (6.1)] alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than Antibody responses to FLUCELVAX were lower in the geriatric (adults physiologic doses) may reduce the immune response to FLUCELVAX. [See 65 years and older) population than in younger subjects. [see Clinical Altered Immunocompetence (5.4)] Studies (14.3) in the full prescribing information] 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy FLUCELVAX® is a registered trademark of Novartis Vaccines and Diagnostics, Inc. Pregnancy Category B: A reproductive and developmental toxicity study has been performed in rabbits with a dose level that was approximately 15 times Manufactured by: Novartis Vaccines and Diagnostics GmbH the human dose based on body weight. The study revealed no evidence of D-35006 impaired female fertility or harm to the fetus due to FLUCELVAX. There are, Marburg, Germany however, no adequate and well-controlled studies in pregnant women. An Affiliate of: Novartis Vaccines and Diagnostics, Inc. Because animal reproduction studies are not always predictive of human 350 Massachusetts Avenue response, this vaccine should be used during pregnancy only if clearly Cambridge, MA USA 02139 needed. 1-877-683-4732

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Accessed 9/4/2013 at www.cdc.gov/flu/about/season/ rotavirus fragment 10 and flagellin iso - that the first such vaccine could be flu-season-2013-2014.htm. lat ed from a salmonella species. 11 available in as little as five years. This 3. Szabo L and Weise E. USA needs more effective flu shots, experts say. USA Today (January 12, 2013). Accessed Interestingly, while antibodies specific optimism has been tempered, however, 8/22/2013 at www.usatoday.com/story/news/nation/ for M2e rarely occur as a natural by results of a number of early-stage 2013/01/11/flu-strains-vaccine/1827677. response to infection with influenza A clinical trials documenting evidence of 4. Fauci A. Better flu vaccine on the horizon (September 3, 2013). Accessed 9/5/2013 at m.cnn.com/primary/ virus, animal and human studies have poor cross-protection or weak immuno - cnnd_fullarticle?topic=newsarticle&category=cnnd_health shown it is possible to induce them genicity of candidate HA- and M2e- &articleId=cnn/2013/09/03/health/better-flu-vaccine- through vaccination. based vaccines. 14 fauci&cookieFlag=COOKIE_SET. 5. Li Y, Myers JL, Bostick DL, et al. Immune history shapes specificity of pandemic H1N1 influenza antibody responses. J Exp Med 2013 Jul 29;210(8):1493-500. 6. Ma W, Kahn RE and Richt JA. The pig as a mixing vessel for influenza viruses: Human and veterinary implications. Despite the panoply of influenza J Mol Genet Med 2009 Jan;3(1):158-66. 7. Steel J, Lowen AC, Wang TT, et al. Influenza virus vaccine based on the conserved hemagglutinin stalk domain. vaccine choices, influenza remains Bio 2010;1:e00018-10. 8. Ekiert DC, Bhabha G, Elsliger MA, et al. Antibody recognition of a highly conserved influenza virus epitope. Science a serious public health threat. 2009;324:246-51. 9. Gilbert SC. Advances in the development of universal influenza vaccines. Influenza Other Respi Viruses 2013 Sep;7(5):750-8. 10. Andersson AM, Håkansson KO, Jensen BA, et al. Increased immunogenicity and protective efficacy of influenza M2e fused to a tetramerizing protein. PLoS One • Nucleoprotein (NP). NP has been Adding another note of caution, this 2012;7(10):e46395. included together with M2e or other year, FDA scientists described their work 11. Turley CB, Rupp RE, Johnson C, et al. Safety and matrix protein in several vaccine candi - with a pig flu vaccine that induced highly immunogenicity of a recombinant M23-flagellin influenza vaccine (STF2.4xM2e) in healthy adults. Vaccine 2011 dates. While NP induces an antibody cross-reactive antibodies against the HA Jul 18;29(32):5145-52. response, it is a vigorous CD8+ T-cell stem region of a different subtype, result - 12. Carragher DM, Kaminski DA, Moquin A, et al. A novel role response in both mice and humans that ing in enhanced — not attenuated — for non-neutralizing antibodies against nucleoprotein in facilitating resistance to influenza virus. J Immunol is thought to account for evidence of severe respiratory disease. The agency 2008;181:4168-76. protective immunity. 12,13 warned that universal flu vaccines that 13. Zhou D, Wu TL, Lasaro MO et al. A universal influenza A Active vaccine development programs target the HA stem region “might vaccine based on adenovirus expressing matrix-2 ectodomain and nucleoprotein protects mice from lethal are scattered across university-based enhance influenza disease rather than challenge. Mol Ther 2010 Dec;18(12):2182-9. laboratories and start-up biopharma - prevent it.” 15 Clearly, there are more 14. Wang L, Zhang H, Compans RW, et al. Universal influenza ceutical firms such as VaxInnate, potential pitfalls ahead for those working vaccine – short review. J Immunol Clin Res 2013 Aug 7;1:1003. Okairos, BiondVax, FluGen and in this complex area of vaccine research. 15. U.S. Food and Drug Administration. FDA-led study Immune Targeting Systems. But despite There is a consensus that solving the describes mechanism potentially responsible for respi - universal agreement about the over - puzzle of the influenza virus’ extraordi - rato ry side effect associated with a pig influenza vaccine. Accessed 9/3/2013 at www.fda.gov/BiologicsBlood whelming need, to date, most large nary evolutionary capacity to escape Vaccines/ScienceResearch/ucm366625.htm. manufacturers of seasonal influenza human immunity will require much more vaccines have hesitated to make a major basic and applied research. Everyone commitment to develop a universal flu agrees on the need for a universal flu KEITH BERMAN , MPH, MBA, is the founder vaccine. vaccine. A key question going forward is of Health Research Associates, providing whether and when government and reim bursement consulting, business development Putting Progress in Perspective industry will commit sufficient and market research services to biopharmaceutical, Beginning a decade ago with the resources to succeed at what by any blood product and medical device manufacturers emergence of a highly pathogenic avian measure is a Herculean challenge. v and suppliers. Since 1989, he has also served as flu virus, worries about a potential editor of International Blood/Plasma News , a pan demic helped spur a flurry of References blood products industry newsletter. research activity focused on development 1. Influenza activity – United States, 2012-13 season and of a universal flu vaccine. By the end of composition of the 2013-14 influenza vaccine. MMWR the last decade, cautious optimism was 2013 Jun 14;62(23):473-9. Credit to Luke Noll, Director of Vaccine Product 2. U.S. Centers for Disease Control and Prevention (CDC). Sales at FFF Enterprises, for contributing being expressed at research conferences What you should know for the 2013-2014 flu season. helpful input for this article.

54 BioSupply Trends Quarterly • October 2013