Evidence review on the immunogenicity, efficacy/effectiveness and safety of typhoid conjugate vaccines

Transcription

1 Evidence review on the immunogenicity, efficacy/effectiveness and safety of typhoid conjugate vaccines SAGE meeting, Geneva, October, 2017 Myron M. (Mike) Levine, MD, DTPH Grollman Distinguished Professor and Associate Dean for Global Health, Vaccinology & Infectious Diseases 1 Center for Vaccine Development, University of Maryland School of Medicine

2 Two typhoid fever vaccines currently recommended by WHO Ty21a live oral strain (licensed in 1980s) Enteric coated capsules (3 or 4 doses) Cannot stimulate Vi antibodies (Vi- negative) Mucosal IgA O and H antibodies Serum O and H antibodies Cell- mediated immunity: o cytokine- production o cytotoxic lymphocytes (CTLs) Purified Vi polysaccharide parenteral vaccine (licensed in early 1990s) Single dose T- independent Serum Vi antibody 2

3 ViPS immunogenicity among children in an endemic area Comparison of anti- Vi antibody levels at three different time points by age group and 95% Cis from studies of immune response to ViPS in Karachi and Kolkata. HepA, hepatitis A vaccine. Ochiai et al. CVI, 2014 Geometric mean concentration Pre- vaccination 6 wks after vaccination 2 yrs post vaccination Pre- vaccination 6 wks after vaccination 2 yrs post vaccination Pre- vaccination 6 wks after vaccination 2 yrs post vaccination 3 Overall (Age 2- <16 years Age 2- <5 years Age 5- <16 years

4 Two post- licensure effectiveness trials of ViPS 4 Kolkata* ViPS Hepatitis A Adjusted Vaccine Efficacy (95% CI) Age, 5-14 yrs N=4282 N=4584 Typhoid cases % (18, 77) Inc./10 5 person days Age, 2-4 yrs N=1097 N=1995 Typhoid cases % (53, 91) Inc./10 5 person days Karachi+ Age, 5-16 yrs N=10,084 N=10,669 57% (6, 81) Typhoid cases Inc./10 3 persons Age, 2-4 yrs N=3154 N=3324 Typhoid cases % (- 192, 35) Inc./10 3 persons

5 Typhoid conjugate vaccine landscape - licensed or in clinical trials* Preclinical stage Phase I Phase II Phase III National licensure Phase 4 studies NIH Vi-rEPA development - not commercialized (Phase I-Phase III efficacy, Infant co-admin) Incepta (A) EuBiologics DAVAC & Finlay Institute Walvax Vi-CRM 197 PT Biofarma (A) Biological E (B) (A) IVI technology transfer (B) NVGH technology transfer SK Chemicals (A) Vi-DT Vi-TT Vi-rEPA LIBP Cadilla (Zydus) BioMed (licensed 2008) Bharat (licensed 2013) Under review 5 * Information available as at Oct 2017

6 Typhoid cases in the Vi-rEPA conjugate vaccine field trial (two doses), 2-5 year olds, Vietnam Vi- repa (N=5525) Placebo (N=5566) Efficacy (95% CI) 27 mos. active follow- up % (77-97%) Cases of TF/10 3 children mos passive follow- up % (22-99%) Cases of TF/10 3 children mos. of total follow- up % (76-97%) Cases of TF/10 3 children Children 2-5 years of age at the time of vaccination were actively followed with household visits for 27- months (per protocol analysis) (F Lin et al 2001) Children were then followed passively (intent- to- treat analysis) for 19 additional months (82% efficacy) (N Mai et al 2003) 46 months efficacy analysis was intent- to- treat (i.e., included recipients of 6 only one dose of vaccine or placebo as well as two- dose recipients)

7 Phase III RCT Overview of Typbar- TCV trials (1) Subjects: children and adults 2-45 years of age; 1 dose TCV; some subjects received a booster at 720 days post- primary dose Comparator ViPS: Typbar; 1 dose plus booster for some subjects, as above Endpoints: GMTs of anti- Vi IgG and % of subjects with anti- Vi IgG titres >4 above baseline Follow- up: up to 5 years post- primary dose Analysis: By all specimens cohort (ASC) and any available specimens group (AAS) 7

8 GMT of anti- Vi IgG in subjects age 2-45 years; primary + homologous booster immunization with Typbar- TCV or Typbar 10 4 ASC TCV ASC ViPS AAS TCV AAS ViPS ASC TCV Not Boosted ASC ViPS Not Boosted AAS TCV Not Boosted AAS ViPS Not Boosted Geometric mean titer (95% CI) Booster 10 0 Day 0 Day 42 Day 720 Day 762 Day 1095 Day 1825 ASC: All specimens cohort; AAS: Any available specimens TCV: typhoid conjugate vaccine (Typbar- TCV); ViPS: Vi polysaccharide vaccine (Typbar) 8 Source of data : Bharat Biotech

9 % subjects 2-45 years with anti- Vi IgG titers >4- fold above baseline; primary + booster immunizations with Typbar- TCV or Typbar 100 Booster ASC TCV ASC ViPS AAS TCV AAS ViPS ASC TCV Not Boosted ASC ViPS Not Boosted AAS TCV Not Boosted AAS ViPS Not Boosted % Subjects with titers ³ 4-fold above Day 0 (95% CI) Day 0 Day 42 Day 720 Day 762 Day 1095 Day ASC: All specimens cohort; AAS: Any available specimens TCV: typhoid conjugate vaccine (Typbar- TCV); ViPS: Vi polysaccharide vaccine (Typbar) Source of data : Bharat Biotech

10 Overview of Typbar- TCV trials (2) Phase III Open Label Trial (OLT) Subjects: children 6-23 months of age given Typbar- TCV; some children received a booster dose 720 days post- primary Endpoints: GMT of anti- Vi IgG and % of subjects with anti- Vi IgG titres >4 above baseline Follow- up: up to 5 years post- primary dose Analysis: By all specimens cohort (ASC) and any available specimens group (AAS) 10

11 GMTs of anti- Vi IgG in children 6-23 months; primary + booster immunization with Typbar- TCV G e o m e tr ic m e a n tite r (9 5 % C I) Booster A S C B o o s te d A A S A S C N o t B o o s te d A A S N o t B o o s te d Day 0 Day 42 Day 720 Day 762 Day 1095 Day 1825 ASC: All specimens cohort; AAS: Any available specimens TCV: typhoid conjugate vaccine (Typbar- TCV) 11 Source of data : Bharat Biotech

12 % children 6-23 months with anti- Vi IgG titers >4- fold above baseline; primary + booster immunizations with Typbar- TCV A S C B o o s te d A A S A S C N o t B o o s te d A A S N o t B o o s te d % S u b je c ts w ith tite rs ³ 4 -fo ld a b o v e D a y 0 (9 5 % C I) Booster 4 0 Day 0 Day 42 Day 720 Day 762 Day 1095 Day 1825 ASC: All specimens cohort; AAS: Any available specimens TCV: typhoid conjugate vaccine (Typbar- TCV) 12 Source of data : Bharat Biotech

13 GMTs of anti- Vi IgG in children 6-11 and months; primary + booster immunizations with Typbar- TCV A S C B o o s te d m A A S B o o s te d m G e o m e tr ic m e a n tite r (9 5 % C I) Booster A S C B o o s te d m A A S B o o s te d m Day 0 Day 42 Day 720 Day 762 Day 1095 Day 1825 ASC: All specimens cohort; AAS: Any available specimens TCV: typhoid conjugate vaccine (Typbar- TCV) 13 Source of data : Bharat Biotech

14 % children 6-11 and months with anti- Vi IgG titers >4- fold above baseline; primary + booster immunizations with Typbar- TCV 100 ASC Boosted 6-11m AAS Boosted 6-11m Booster ASC Boosted 12-23m AAS Boosted 12-23m % Subjects with titers ³ 4-fold above Day 0 (95% CI) Day 0 Day 42 Day 720 Day 762 Day 1095 Day 1825 ASC: All specimens cohort; AAS: Any available specimens TCV: typhoid conjugate vaccine (Typbar- TCV) 14 Source of data : Bharat Biotech

15 Anti- Vi IgG antibody avidity index (AI) in Typbar & Typbar- TCV recipients after primary + booster immunization with 95% CI 15 Mohan et al; CID 2015

16 % subjects with Avidity Index (AI) values > 60 at Days 42, 720 and 1825, without a booster vaccination at Day 720 No booster 16 Source: Bharat Biotech

17 % subjects with Avidity Index (AI) values > 60 at Days 42, 720, 762 and 1825, with a booster vaccination at Day 720 With booster 17 Source: Bharat Biotech

18 Overview of Typbar- TCV trials (3) Co- administration of Typbar- TCV with measles (at 9 mos) and MMR (at 15 mos) Subjects & comparison: infants 9 mo old who received Typbar- TCV + measles vaccine vs infants who received Typbar- TCV alone at age 8 mo OR at age 10 mo MMR vaccine at 15 mo of age, alone OR concomitantly administered Typbar- TCV Endpoints: GMTs of anti- Vi IgG and anti measles IgG at variable timepoints depending on % of subjects with anti- Vi IgG titres >4 above baseline Follow- up: up to 2 years post- primary dose Analysis: non- inferiority analysis of non- interference of anti- Vi IgG and anti- measles IgG 18

19 Non- interference of Typbar- TCV with measles antibody: Proportion with fourfold rise above baseline at day Source of data : Bharat Biotech

20 Non- interference of measles vaccine with Vi antibody response: proportion with fourfold rise above baseline at day Source of data : Bharat Biotech

21 Overview of Typbar- TCV trials (4) A second RCT of Typbar- TCV vs ViPS, using the WHO prequalified ViPS (Typhim Vi, Sanofi Pasteur) Subjects: children 2-15 years of age Endpoints: as for Phase III RCT Follow- up: 210 days post- primary vaccination Similar overall conclusion as in Phase III RCT; TCV was more immunogenic than the ViPS. The key difference here is the ViPS is a WHO prequalified vaccine (data relevant for the PQ process). 21

22 Lancet publication online September 28, 2017;; Randomized controlled, double-blinded Phase 2b study in immunologically naïve adult volunteers (UK) Used established controlled human infection model (1-5 10⁴ CFU of S. Typhi Quailes strain, with buffer) Subjects aged 18 to 60 years Oral challenge 1 month post-vaccination single dose Vi-TT (Typbar-TCV, N=37) single dose Vi polysaccharide (Typhim Vi, N=35) control group (ACWY meningococcal conjugate vaccine, N=31) 22

23 Human challenge model for Vi- TT conjugate vaccine VE against variable endpoints 54.6% (95% CI, ) for Vi- TT vs 52.0% (95% CI, ) for Vi- PS against primary endpoint of bacteraemia or persistent fever 87.1% (95% CI, %) for Vi- TT vs 52.3% ( ) for ViPS against fever 38 C for >12 hours followed by Jin et al. Lancet 2017 positive blood culture Vi- TT VE range between 37.2% and 89.5% for bacteraemia alone or clinical diagnosis respectively GMTs, seroconversion and quality of immune response Good correlation between higher anti- Vi GMT & lower risk of disease BUT no absolute threshold of protection Clinical & biological parameters in response to challenge 23

24 24 Maryland & Oxford volunteer challenges with Ty21a University of Maryland * Controls Ty21a Endpoint of typhoid No. challenged % Vaccine Efficacy (95% CI) University of Oxford + Endpoint of typhoid No. challenged % Vaccine Efficacy (95% CI) Bacteraemia following fever Controls Vaccinees N=43 N=28 87% (95% CI, 48, 97) Bacteraemia following fever Controls Vaccinees N=30 N=30 80% (95% CI, 16%, 95) * Gilman RH et al. J Infect Dis 1977; 5-8 doses, cfu/dose + Darton T et al. PLOS NTD 2016; 3 enteric capsule doses, 10 9 cfu

25 Safety of typhoid vaccines Global Advisory Committee on Vaccine Safety (GACVS) conclusions - Dec 2016 (WER 2017; 2 (92): 13 20) Both ViPS and Ty21a have a good safety profile estimated use in several million and several hundred thousand doses respectively over 3 decades no safety signals reported AE profile for TCV similar to ViPS and no safety signals reported but available data limited post- marketing data from private sector largely passive; no SAEs reported to the manufacturer Recommendations for further safety monitoring Phase 2b human challenge study (Jin et al. Lancet. 2017) 4 SAEs reported in human challenge study (3 in TCV and 1 in ViPS groups) DSMB assessed all SAEs as not related to vaccination 25

26 GRADE assessment - Sample 26 Source: Cochrane Response and Cochrane Infectious Diseases Group

27 27 Conclusions about the evidence on TCV Safety & clinical tolerability Excellent, like other conjugates Immunogenicity Stronger, more durable serum IgG anti- Vi response than ViPS Higher avidity anti- Vi than after ViPS No interference when co- administered with measles vaccine at age 9 months or MMR at 15 months Booster after 2 years restores waning titers, enhances avidity A notable proportion of young Indian children given a single dose of Typbar- TCV at 6-23 mos. of age still had elevated titers (> 4- fold over baseline) 3 years (~80%) & 5 years (~75%) later B memory cell measurement in naïve UK adults being analyzed

28 Efficacy Evidence from 3 controlled trials of 3 products Vi- repa - 89% VE in 3-5 year old Vietnamese children over 46 mos of follow- up in well- designed RCT Typbar- TCV - 87% VE in volunteer challenge study in Oxford PedaTyph (Vi- TT) methods not well described Conclusions about the evidence on TCV (2) no TF cases among 905 Indian children (mostly school age) given 2 Vi- TT doses vs 11 cases among 860 unvaccinated controls followed for 12 mos 28

29 Acknowledgments Dr Amanda Buskirk, Post doctoral fellow, Center for Vaccine Development (CVD), University of Maryland Professor William Blackwelder, Head, Biostatistics Unit, CVD Professor Marcela Passetti, Chief, Applied Immunology Section, CVD 29