Case presentation of non-clinical and clinical development of vaccines Jankovics,István

UNIVERSAL INFLUENZA VACCINE

The Flu Virus: Unpredictable, Fast Mutating Seasonal Flu Per year: 23,000 deaths1 (21,000 elderly) & 200,000 hospitalizations2 in just the US 8th leading cause of death3 (US), Worldwide death toll of 250,000-500,000 annually4 $87B economic burden5 in the US of which $56B is in the elderly Pandemic Flu When?… Where?... Which?… pandemic strain Pandemic strain: a new to Humans Past century: 4 major pandemics with over 100M deaths5 The 1918 Spanish Flu cost to global GDP6 was 4.8% or over $3T in today’s dollars 1 http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5933a1.htm#tab2; 2 http://www.cdc.gov/flu/about/qa/disease.htm; 3 http://www.cdc.gov/nchs/fastats/deaths.htm; 4 http://www.who.int/mediacentre/factsheets/fs211/en/ 5 Molinari et. al, The annual impact of seasonal influenza in the US, Vaccine 25 (2007) 5086–5096; 6 1918 Influenza: the Mother of All Pandemics, Volume 12, Number 1—January 2006, CDC; 7 World Bank 2014:Pandemic Risk

Current Vaccines limitations Strain specific – mismatch between vaccine strains and seasonal circulating strains Limited efficacy of pandemic vaccines based on HA At risk populations: Elderly, young children Long Production (avian strains kills hen egg embryo, 4-6M) Hen egg Allergy (5% of adults)

Trends in the Industry UNIVERSAL New adjuvants (e.g. Novartis (now bioCSL), GSK, Novavax) Passage from egg to cell culture (NovaVax, Protein science) New delivery: Intradermal, Intranasal, Oral (Sanofi, Vaxart…) DNA vaccines (Pfizer/PowderMed, Inovio…) Recombinant rHA (e.g. Protein Sciences, VaxInnate…) UNIVERSAL Stem HA: (Crucell, Sanofi) M2e (Flugen) Polypeptides: (BiondVax, SEEK…)

BiondVax Schematic structure and peptide sequence of theMultimeric-001 vaccine

Peptid-1.:PKYVKQNTLKLAT Peptid-2: SKAYSNCYPYDVPDYASL

http://www.unisecconsortium.eu/

Purpose "Multimeric-001" (M-001) contains conserved, common linear influenza epitopes that activate both cellular and humoral arms of the immune system against a wide variety of influenza A and B strains. Apart from its direct action, M-001 is an attractive candidate for priming immune responses to pandemic influenza vaccine in the adult population. The current clinical study was designed to assess M-001's standalone and priming action in subjects aged 18-60 years old. This is a Phase IIb study comprising 222 participants. Eligible subjects were randomized to receive two sequential intramuscular injection of 0.5mg or 1.0mg M-001 (treatment), or two placebo (saline) injection, before receiving the sub optimal dose of H5N1 pandemic vaccine.

Primary Outcome Measures: For each vaccine group the incidence rate of subjects with solicited AE(s) with 95% confidence interval [ Time Frame: Day 0 to Day 42 (21 days after the last M-001 dosing) ]All subjects For each vaccine group the percentage of subjects with SAE(s) with 95% confidence interval [ Time Frame: Day 0 to Day 180 (study conclusion) ]All subjects For each vaccine group the influenza-specific cellular immune responses evaluated by multi-parametric FACS analysis [ Time Frame: Days 0 and 42 (21 days after the last M-001 dosing) ]All subjects Secondary Outcome Measures: For each vaccine group the antibody responses to the H5 vaccine strain evaluated by hemaglutination inhibition (HI) assay [ Time Frame: Days 0 and 63 (21 days after the H5N1 immunization) ]All subjects Other Outcome Measures: Exploratory: For each vaccine group the antibody responses to the non-H5 vaccine strains evaluated by hemaglutination inhibition (HI) assay [ Time Frame: Days 0 and 63 (21 days after the H5N1 immunization) ]All subjects Exploratory: For each vaccine group the influenza-specific cellular immune responses evaluated by quantitative reserve transcription polymerase chain reaction (qRT-PCR) assay [ Time Frame: Days 0, 42 and 63 ]In all groups, in a subset of 60 subjects Exploratory: For each vaccine group the antibody responses to the H5 vaccine strain evaluated by single radial hemolysis (SRH) assay [ Time Frame: Days 0 and 63 (21 days after the H5N1 immunization) ]All subjects Exploratory: The association between cellular immune markers and humoral immune responses will be examined. [ Time Frame: Days 0, 42 and 63 ]

Detailed Description: This is a multi-center, randomized, double blind active-controlled Phase 2b study. 222 subjects will be randomized 1:1:1 into three groups to receive two sequential non-adjuvanted 0.5 mg or 1.0mg intramuscular injection of M-001 (treatment), or two placebo (saline) injection, before receiving the Alum adjuvanted H5N1 vaccine at a sub optimal dose of 3mcg. Hemagglutinin inhibition (HAI) will be evaluated at baseline and 3 weeks after H5N1 whole virion inactivated pandemic influenza vaccination as a measure of M-001's ability to enhance the humoral response. Cell mediated immune (CMI) responses will also be evaluated at baseline and after immunization with M-001 as a measure of M-001's standalone immunogenicity. The subjects will monitored for safety throughout the study until day 18

Lab tests

A/H5N1

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