ESCMID Online Lecture Library

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1 Vaccines against norovirus state of the art, trials in children and adults Hugues Bogaerts MD global vaccine consultant at H+B 3rd ESCMID Conference on Vaccines

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3 Between Jan and 22 Dec 2014, 689 outbreaks were reported. Ninety-three per cent resulted in ward/bay closures or restrictions to Admissions and 67% (459) were laboratory confirmed as due to norovirus. 2

4 Norovirus The perfect human pathogen (CDC 2012) 1 Highly infectious 1 Infection Rapidly and prolifically shed, difficult to avoid 1 Transmission Violent vomiting and uncontrolled diarrhoea favour transmission 1 Pathophysiology Symptomatology Evokes limited immunity in many people 1 1. Hall AJ J Infect Dis 2012

5 Norovirus disease is underreported Many more cases occur in the community than those reported to health authorities - UK estimate: almost 300 community cases for each case reported to national surveillance 1 ~294 community cases GP: General Practitioner Figure adapted from Tam et al. Gut ~13 cases presenting to GP 1 reported to national surveillance Norovirus burden is underestimated because it remains substantially underdiagnosed and underreported 2,3 - UK estimate: <5% of patients experiencing endemic norovirus-related disease presented to a physician 1 - US estimate: only ~10% of individuals with norovirus gastroenteritis seek medical attention 4 1. Tam CC Gut 2012; 2. Koopmans M J Hosp Infect 2009; 3. Beersma MF J Clin Microbiol 2012; 4. CDC MMWR 2011

6 Norovirus: Age related Impact A substantial part of the severe norovirus-related clinical burden in industrialised countries is in older adults % of nosocomial norovirus infections occur in older individuals ( , Germany) 1 Discharge Rate/100,000 person years Norovirus-related hospital discharge rates/100,000 person-years in US ( ) Figure adapted from Lopman B et al. CID >= 85 Age (Years) 1. Spackova M Infect Control Hosp Epidemiol 2010; 2. Glass RI NEJM 2009; 3. Trivedi TK Am J Infect Control 2013; 4.Hall AJ Emerg Infect Dis 2013; 5. Lopman B Clin Infect Dis2011

7 Total estimated Cost per year of Norovirus ~USD 5.5B (US) and ~USD 4 B (EU) United States Hospital Costs Other Costs USD 5.5 B 1 / 5,000 QALYs 5 per year USD 4 B per year 1,2 5, , (49%) 73 (15%) 180 (36%) Older Adults Children (<5y) Other Total medical costs for children: $273m 7 3,990 20% 80% Healthcare Costs Societal Costs In the UK, an estimated 18.8 M school / working days are lost 3 USD 141 M per year 4 1 Bartsch SM Vaccine 2012; 2 Hoffman S J Food Prot 2012; 3 Tam et al. Gut 2012; 4 Mangen RIVM 2013; 5 Batz M et al. Journal of Food Protection Lopman BA Clin Infect Dis 2011; 7 Payne DC NEJM 2013; EU cost estimates are based on an exchange rate of 1=US$1.33 EU 2% % 6% Indirect Healthcare Costs Direct Healthcare Costs Direct Non-Healthcare Costs 6

8 Vaccine candidate development Obstacles Difficult to culture in vivo Hampers the development of live, attenuated vaccine strains No animal model Human virus doesn t reliably infect, replicate or cause illness in animals Limits the testing of vaccine candidates for protective responses First isolated in 1968 (Norwalk), not sequenced until 1989 But, after which sensitive diagnostic test could be developed and implemented 7

9 From virus to vaccine candidates Viral gastroenteritis outbreak in Norwalk, Ohio 1 Genome sequence published by Baylor College group 2 Expression of norovirus VLPs & formulation of candidate vaccine by Baylor College group VLP = Virus-like particle Discovery by Dr. Albert Kapikian, NIH 1 First PCR confirmation in stool samples 3 norovirus candidate vaccine developments 1. Kapikian AZ J Virol 1972; 2. Xi JN Science 1990; 3. Jiang X J Clin Microbiol 1992; 4. Jian X J Virol Methods 1999; 5. Ball JM Gastroenterology 1999;

10 GII.4: dominant genotype worldwide 1 GII.4 is the dominant genotype around the world 1 US ( ) 3 England and Wales ( ) 5 Brazil ( ) 6 Germany ( ) 4 China ( ) 2 Japan (2008) 7 GI GII.4 Other GII Mix 1. Hoa Tran TN J Clin Virol 2013; 2. Yu Y Biomed Res Int 2014; 3. Zheng DP J Clin Microbiol 2010; 4. Bernard H Epi Infect 2014; 5. PHE report 13 Feb 2014; 6. Ferreira MS J Med Virol 2010; 7. Inaida S PLoS One 2013

11 Candidate Norovirus Vaccines Candidate Preclinical Phase I Phase II Phase III University of Arizona 1 bivalent noro VLPs GI.1 & GII.4 University of Tampere 2 Trivalent Noro VLPs: GI.3 & GII.4 Rotavirus: rvp6 Cincinnati Children s Hospital 3 P particle of VP1 Rotavirus: rvp8 Takeda Noro VLPs GI.1 & consensus GII.4 Various lab animals intranasal BALB/c mice BALB/c mice Planned Velasquez L et al, Vaccine July 18; 29(32): ; 2.Tamminen K et al, PLoS One, July 2013 Volume 8 Issue 7 e70409;

12 Candidate Norovirus Vaccines Candidate Preclinical Phase I Phase II Phase III University of Arizona bivalent noro VLPs GI.1 & GII.4 Various lab animals intranasal Intranasal delivery of GelSite based VLPs induces robust systemic and mucosal immunity in animals 11 Velasquez LS et al, Vaccine 2011;29:

13 Candidate Norovirus Vaccines Candidate University of Tampere Trivalent Noro VP1 VLPs: GI.3 & GII.4 Rotavirus: rvp6 Preclinical c e L e lin BALB/c mice Intramuscular n O D or I M h t C u S a E by 12 Tamminen K et al, PLoS One, July 2013 Volume 8 Issue 7 e70409 r b i L e r tu y r a

14 Candidate Norovirus Vaccines Candidate Preclinical Phase I Phase II Phase III University of Tampere Trivalent Noro VP1 VLPs: GI.3 & GII.4 Rotavirus: rvp6 BALB/c mice Intramuscular High levels of NoV and RV type specific serum IgGs with high avidity (>50%) as well as intestinal IgGs were detected in the immunized mice. Cross-reactive IgG antibodies were elicited against heterologous NoV VLPs not used for immunization (GII-4 NO, GII-12 and GI-1 VLPs) NoV-specific serum antibodies blocked binding of homologous and heterologous VLPs to the putative receptors, histo-blood group antigens, suggesting broad NoV neutralizing activity of the sera 13 Tamminen K et al, PLoS One, July 2013 Volume 8 Issue 7 e70409

15 Candidate Norovirus Vaccines Candidate Preclinical Phase I Phase II Phase III Cincinnati Children s Hospital P particle of VP1 Rotavirus: rvp8 BALB/c mice NoV P domain complexes are efficiently presented by DCs to elicit humoral and cellular immune responses 14 Fang H et al, PLoS One 2013;8: e Tan M et al, J Virol Jan. 2011, p

16 Candidate Norovirus Vaccines Candidate Preclinical Phase I Phase II Phase III University of Arizona 1 bivalent noro VLPs GI.1 & GII.4 University of Tampere 2 Trivalent Noro VLPs: GI.3 & GII.4 Rotavirus: rvp6 Cincinnati Children s Hospital 3 P particle of VP1 Rotavirus: rvp8 Takeda Noro VLPs GI.1 & consensus GII.4 Various lab animals intranasal BALB/c mice BALB/c mice Planned Velasquez L et al, Vaccine July 18; 29(32): ; 2.Tamminen K et al, PLoS One, July 2013 Volume 8 Issue 7 e70409;

17 Takeda s Norovirus Vaccine Candidate Selection of antigens GI.1 VLPs broadly cross-react with other GI strains Norwalk selected as GI antigen in Takeda vaccine GII.4 is the natural choice for a GII antigen due to its dominance worldwide Takeda developed a consensus VLP from three relevant GII.4 strains 2006a (Yerseke) 2006b (Den Haag) 2002 (Houston) Figure from Glass et al., NEJM 2009;361: Glass RI NEJM 2009

18 Takeda s Norovirus Vaccine Candidate G.II Consensus VLP Consensus strategy presents epitopes from three different norovirus GII.4 strains on one virus-like particle antigen 17

19 Takeda s Norovirus Vaccine Candidate Composition Virus-Like Particles (VLP) Consensus VLP + NoV VLP Antigen - source: Takeda ADJUVANTS Al(OH) 3 Aluminum hydroxide ± MPL 3-O-desacyl-4 monophosphoryl lipid A 18 Garçon,N. et al. (2011c). Role of AS04 in human papillomavirus vaccine: mode of action and clinical profile. Expert. Opin. Biol. Ther. 11,

20 Takeda s Norovirus Vaccine Candidate Clinical Development Program Aim: To show the safety, immunogenicity in all age groups To demonstrate efficacy Worldwide registration Indications: Plan 1: Individuals aged 9 years and older Plan 2: Children from 6 weeks to <9 years Phase I/ II trials in different age groups : Confirm dosage, composition, number of doses, schedule Assess safety and immunogenicity Phase III studies will evaluate: Safety in infants, children, adolescents, adults and elderly Clinical efficacy (young adults, infants) & immunobridging to older adults Lot-to-lot consistency Concomitant vaccine use Long-term follow-up for safety and immunogenicity (up to 5 years) 19

21 Takeda Norovirus Vaccine Candidate Ph I Healthy Adults years - Trial LV Safety and immunogenicity study Randomized, double blind, placebo-controlled, dosage-and-age escalation: Doses: 5/5; 15/15; 50/50 and 150/150 µg per VLP, adjuvanted with MPL and Al(OH) 3 Healthy adults in different age strata (N = 102), 18 49, 50 64, years of age Two doses, 28 days apart 20 Treanor JID 2014

22 Takeda Norovirus Vaccine Candidate Ph I Healthy Adults years - Trial LV Solicited AEs No dose-related effect No increase after Dose 2 Headache* was the most frequent solicited systemic AE Tenderness* and pain* were the most frequent solicited local AE AEs were primarily mild or moderate in severity Solicited systemic AEs Any Systemic Symptom Nausea Abdominal Cramps/Discomfort Diarrhea Vomiting Headache Fatigue/ Malaise Muscle Aches Joint Aches Chills Elevated Oral Temperature Solicited local AEs Any Injection Site Symptom Tenderness Pain Swelling Redness Reactogenicity Placebo (N=9) mild mod. sev Placebo (N=9) mild mod. sev. 5/5 VLP (N=10) 5/5 VLP (N=10) 15/15 VLP (N=10) Frequency (%) 15/15 VLP (N=10) Frequency (%) Post-Dose 1 50/50 VLP (N=10) 50/50 VLP (N=10) 150/150 VLP (N=9) * * * * * 150/150 VLP (N=9) * * * * * * * 21 Treanor JID 2014

23 Takeda Norovirus Vaccine Candidate Ph I Healthy Adults years - Trial LV Immunogenicity of the selected 50/50 µg dosage (n=102) Increases in serum antibodies to each of the VLPs (GI.1 and GII.4) Immune responses observed at Day 7 (the earliest time point measured) No further titer increases after the 2 nd dose Serum antibodies persist 12 months after vaccination Similar response by age group Pan IgG IgG IgA 22 Treanor JID 2014

24 Takeda Norovirus Vaccine Candidate Ph I Healthy Adults years - Trial LV Breadth of response of the 50/50 µg dosage Vaccination induces HBGA blocking antibody response against strains and types not included in vaccine Consensus GII.4 VLP induced antibody response against Sydney 2012 GII.4 strain that emerged only 1-2 years later 23 Baric et al., Fifth International Conference on Calicivirus, 2013

25 Takeda Norovirus Vaccine Candidate GII.4 Challenge Study in healthy adults - Trial LV Safety, immunogenicity, and efficacy study Phase I/II randomized, double blind, multi-center, placebo-controlled Healthy adults (N=132), years of age: Two doses of NoV vaccine (50/50 µg per VLP), 28 days apart Challenge on study day 56 with live GII.4 norovirus by oral administration (strain was different than the vaccine, similar to season-to-season variability) Vaccination Stage, with post-vaccination follow-up Vaccine was generally well tolerated, no vaccine-related serious adverse events reported Challenge Stage, with post-challenge follow-up 109 vaccinees challenged Design 24 Bernstein JID 2014

26 Takeda Norovirus Vaccine Candidate GII.4 Challenge Study in healthy adults- Trial LV Gastroenteritis Symptom (post-hoc analysis) Severe vomiting AND/OR diarrhea Moderate or severe vomiting AND/OR diarrhea Mild, moderate or severe vomiting AND/OR diarrhea Per Protocol Clinical efficacy Vaccine (%) N = 50 Placebo (%) N = 48 Rate Difference (95% CI) % Reduction (95% CI) p value (Fisher s Exact) 0 (0.0%) 4 (8.3%) -8.3 (-16.2, -0.5) 100% (-,-) (6.0%) 9 (18.8%) (-25.6, 0.1) 68% (-11.2, 90.8) (20.0%) 20 (41.7%) (-39.5, -3.8) 52% (8.3, 74.9) Vaccination associated with reduction in vomiting and diarrhea Secondary endpoint by modified Vesikari score (p=0.023) Fecal viral shedding was lower in vaccinees Primary endpoint not met, informs design of efficacy trial planned illness definitions and serum and stool assays flawed (PCR, 4-fold increase) 25 Bernstein JID 2014

27 Conclusions Norovirus related disease burden is substantial and likely underestimated The disruption caused by outbreaks causes significant costs Challenge studies indicate that vaccination can have a meaningful clinical impact Takeda s candidate VLP norovirus vaccine in adults Is generally well-tolerated Elicits an immune response after one dose Produces functional HGBA-blocking antibody responses Induces cross-blocking seroresponses May reduce viral shedding Development is proceeding into Phase 3 in adults, and then in children 26

28 27 Thank you