NEXT GENERATION ROTAVIRUS VACCINES - WHO

NEXT GENERATION ROTAVIRUS VACCINES

WHO Product Development for Vaccines Advisory Committee

26-27 June 2018

Duncan Steele, Carl Kirkwood, Lyou-Fu Ma

Confidential and proprietary data

© 2014 Bill & Melinda Gates Foundation

© Bill & Melinda Gates Foundation | 2

Robust pipeline of live, attenuated oral rotavirus vaccines

• WHO pre-qualified and globally introduced

• Nationally licensed and in use in country

• New vaccines in development

Global impact of rotavirus vaccines

• Global status of rotavirus vaccine introductions

• Global impact and vaccine effectiveness

Rationale for developing parenterally delivered, non-replicating rotavirus vaccines

• Modest efficacy and effectiveness of the current live, attenuated rotavirus vaccines => better efficacy

• Potential increased safety profile of non-replicating rotavirus vaccines

• Opportunity for combination vaccines with routine childhood vaccines

• Potential lower COGS

• Potential for alternative immunization schedules

CURRENT SCENARIO FOR ROTAVIRUS VACCINES

CONFIDENTIAL

LIVE ATTENUATED, ORAL ROTAVIRUS VACCINES

Vaccine pipeline is diverse including: • Multiple live-attenuated oral vaccines • Non-replicating candidates “Current” licensed generation vaccines: • Three WHO PQed products • National licenses, mainly in private

market • These aim to match performance of

Rotarix/RotaTeq vaccines • Offer domestic mfg. options, add to

supplier base / sustain competition Next generation parenteral vaccines • Aim to exceed / meet performance of

Rotarix/RotaTeq vaccines • Offer potential additional safety • Offer potential lower costs • Offer potential combination

opportunities for increased coverage

WHO PQ

DCVMs include: Bharat Serum BioFarma Hilleman Polyvac Wuhan Shantha Butantan Langzhou

Liquid presentation Bharat Biotech

ROTAVAC Bharat Biotech

Live

-att

en

uat

ed

, o

ral Lamb rotavirus

Lanzhou Institute of Biological Products

Liquid BRV Serum Institute

Liquid BRV Shantha Biotechnics

Rotavin Polyvac, Vietnam.

RotaSIIL Serum Institute

RV3-BB Biofarma, Indonesia

Liquid BRV WUHAN China

Liquid BRV BUTANTAN Brazil

Discovery & preclinical

Phase 2 Phase 3 Market Phase 1

Live

-att

en

uat

ed

o

ral (

WH

O P

Q)

RotaTeq Merck

Rotarix GSK

Heat stable pentavalent Hilleman

MSD, India

Dormant

National license


© Bill & Melinda Gates Foundation | 4 Source: International Vaccine Access Center (IVAC), Johns Hopkins Bloomberg School of Public Health. VIEW-hub Global

Vaccine Introduction and Implementation Report, June20, 2018

New Gavi country introductions

2017: Lesotho, Cote D’Ivoire, Pakistan (phased national introduction

ongoing)

2018: Afghanistan, Uganda, DRC, Nepal, Benin, Bangladesh (Uttar

Pradesh will also introduce)

2019 (expected): Nigeria*, CAR, Myanmar, Lao PDR

GLOBAL ROTAVIRUS VACCINE INTRODUCTIONS

92 countries have introduced by December 2017

ROTAVIRUS VACCINE EFFICACY (PRE-LICENSURE) WAS SIMILAR IN

SIMILAR SETTINGS (i.e. HIGH AND LOW INCOME COUNTRIES)

US/Finland/Other

RotaTeq 98% (88.3,100)

Africa

RotaTeq 64.2% (40.2, 79.4)

Rotarix 61.7 % (44.0, 73.2)

Southeast Asia

RotaTeq 51.0% (12.8, 73.3)

India

ROTAVAC 56.3% (12.8, 73.3)

Efficacy against severe rotavirus disease in first year of life

Vesikari T, Matson DO, Dennehy P et al. NEJM 2006; 354:23-33; Ruiz-Palacios GM, Perez-Schael I, et al. NEJM 2006; 354:11-22; Madhi SA, Cunliffe NA, Steele AD et al. NEJM 2010; 362:346-

357; Zaman K, Anh DD, Victor CV et al. Lancet 2010; 376:615-23; Armah GE, Sow S, Breiman RF et al. Lancet 2010; 376:606-614; Bhandari N, Rongsen-Chandola T, Bavdekar A, et al. Lancet

2014; 383:2136-43; Isanaka S, Ousmane G, Langendorf C, et al. NEJM 2017;376:1121-30; Kulkarni PS, Desai S, Tewari T, et al. Vaccine 2017; 35:6228-37

Latin America/Finland

Rotarix 84.7% (71.7,92.4)

5

Southeast Asia (high)

Rotarix > 96%

© Bill & Melinda Gates Foundation |

George Armah

Nigel Cunliffe

Samba Sow

Shabir Madhi

K Zaman

PK Kulkarni

India

RotaSIIL 36% (11.7, 53.6)

Niger

RotaSIIL 66.7% (49.9, 77.9)

Sheila Isanaka Dang Duc Anh

Nita Bhandari

Bill & Melinda Gates Foundation | 6

SUMMARY OF ROTAVIRUS VACCINE EFFECTIVENESS STUDIES

57 articles from 27 countries

Among children <5 years of age, the median percentage reduction in

AGE hospitalizations 38% overall and 41%, 30%, and 46% in countries with low, medium,

and high child mortality, respectively

Hospitalizations and emergency department visits due to rotavirus AGE were reduced by a

median of 67% overall and 71%, 59%, and 60% in countries with low, medium, and high child

mortality, respectively Reduction in mortality due to acute gastroenteritis

Burnett E, Jonestellar CL, Tate J et al, J Infect Dis. 2017; 215:1666-72

Gastanaduy P, Sanchex-Uribe E, Esparza-Aguilar M, et al. Pediatrics 2013; 131(4): e1115-20


ROTAVIRUS DISEASE BURDEN AFTER ROTAVIRUS VACCINE INTRODUCTION

Attributable proportion of rotavirus severe diarrhea is still high, despite vaccine introduction and

uptake in African countries (provisional unpublished data)

Kenya (RVIDA, 1st year data) Tanzania

CONFIDENTIAL Source: Karen Kotloff, UMD and Eric Houpt and colleagues, UVA

• Despite enormous success of live attenuated, oral rotavirus vaccines several issues remain:

o A lower protective efficacy in the first 1-2 years of life (~50-60%) in developing countries in Asia

and Africa against moderate-to-severe rotavirus diarrhea

o Waning efficacy in the second year of life with little evidence of protection in the second year as

compared to the protection in "high-income“ countries (>95%)

o Limited indirect protection in impoverished, high risk settings

• Lower national coverage of rotavirus vaccine than DPT-3 / pentavalent vaccine rates in most

countries

• Vaccine costs are still relatively high.

• Despite an overall acceptable safety profile, intussusception rate seems to be slightly

increased by the live oral rotavirus vaccination (occurrence 1 to 3 /100 000 vaccine

recipients) in developed countries

Thus non-replicating, parenterally delivered rotavirus vaccines may provide viable alternative


WHAT HAVE WE LEARNT ABOUT LIVE, ORAL ROTAVIRUS VACCINES?

CONFIDENTIAL

CHALLENGES FOR ORAL ROTAVIRUS VACCINES

• Transplacental maternal

antibodies

• Breast milk antibodies

• Stomach acid/proteases

• Co-administration of other

vaccines

• Nutritional status

• Environmental enteropathy

• Microbiota

• Micronutrient deficiency

• Early & constant exposure

to other gut pathogens

• Other co-morbidities

Factors that lower

virus titre

Factors that affect

antibody responses

9 Glass RI, Jiang B, Parashar U. Vaccine 2018; 36:2233-36; Patel M, Shane AL, Parashar U et al, J Infect Dis 2009; 200:39-48

Multiple clinical immuno studies • 2 v 3 doses of Rotatrix

• With/without breastfeeding

• Interference from maternal ab

• Interval between doses

• Booster dose at 9 mo

• Enteric pathogen interference

• Zn / probiotic co-administration

Multiple host studies • Microbiome

• Blood group antigen /Lewis

secretor status

• Environmental enteropathy


NON-REPLICATING, PARENTERAL ROTAVIRUS VACCINES

10

Discovery Phase 2 Phase 3

Expressed

VP6 protein

No

n r

eplic

atin

g

Inactivated Rotavirus CDC/SII

VLP VP2/6;

VP2/6/7

NRRV (P2-VP8*) PATH

Combo- VP6 with

norovirus VLP

Potential benefits include:

• Lower COGs

• Higher efficacy profile

• Decreased signal of intussusception

• Potential for use in combination vaccine

• Potential for alternative dosing schedules

Pre-clinical

CONFIDENTIAL

Phase 1 Licensure


• Developed by PATH, using NIH constructs. • SK Vaccines, Korea - commercial partner

• Trivalent vaccine candidate based on: • truncated VP8 subunits of P[4], P[6] and P[8]

genotypes (major circulating human rotavirus

genotypes)

• fused to tetanus toxin P2 CD4 epitope

• expressed in E.coli (T7 promoter)

• adsorbed to aluminum hydroxide

• parenteral IM administration route


NON-REPLICATING ROTAVIRUS VACCINE (NRRV – P2-VP8* TV)

*

*

ΔVP8*

Fusion domain

Hsc70 binding

site

*

*

Wen X et al. Vaccine 2014; Wen X et al. HVI 2015

VP7 outer capsid

VP4 hemagglutinin

VP6 inner capsid

Phase 1 safety study in US adults

Monovalent P2-VP8* P[8] was well

tolerated and immunogenic

• 4-fold rises of both IgA and IgG

responses observed

• Increasing GMTs with dose and titres

• Homologous N-Abs observed in ~50%

of subjects

• Responses to P[4] and P[6] had lower

GMTs


CLINICAL DEVELOPMENT OF P2-VP8* MONOVALENT CANDIDATE

Phase 2 age-descending, dose-escalating study of the

monovalent vaccine candidate (P2-VP8* P[8]) in toddlers

and infants in South Africa

Serum antibody geometric mean titres (unadjusted)

Fix A, Harro C, McNeal M et al. Vaccine 2015; 33:3766-72; Groome MJ, Koen A, Fix A et al, Lancet Infect Dis 2017; 17:843-53


Serum antibody responses

Shedding of Rotarix after 3-dose P2-VP8* vaccine

PHASE 2 SAFETY/IMMUNOGENICITY

IN TODDLERS AND INFANTS

Groome MJ, Koen A, Fix A et al, Lancet Infect Dis 2017; 17:843-53

14

AGE-DESCENDING, DOSE-ESCALATING STUDY OF THE TRIVALENT P2-

VP8* VACCINE IN SOUTH AFRICAN INFANTS

• Phase 1/2 study in South Africa – initiated in March 2016

• Healthy adults, toddlers and infants

• Dose-escalation: 15 => 30 => 90 µg of total antigen

• Infants received 3 IM doses, one month apart, co-administered with EPI vaccines

• Enrolled in two stages, DSMB review before progression to Phase 2

• Enrollment closed in May 2017 – 558 infants enrolled

• Final visit for primary data (28 days after last study vaccination) – 18 August 2017

• All dose-levels in infants well tolerated and no safety signals observed

• Immunogenicity results showed robust immune responses (n=139/arm)

A priori “go” criteria were met and a decision to progress to Phase 2b/3 efficacy study,

with early futility read.

CONFIDENTIAL © Bill & Melinda Gates Foundation |

CONFIDENTIAL Bill & Melinda Gates Foundation | 15

TWO DATA SLIDES WITHHELD OF THE P2-VP8* TRIVALENT CLINICAL TRIAL IN SOUTH AFRICA


INACTIVATED ROTAVIRUS VACCINE (IRV) WITH GROWTH AND

STABILITY

>99% TLP

G1P8 G2P4

● 107 ~ 108 titer in Vero cells

● Predominant (>90%) triple-layered

● Stable during USP & DSP

~ 107 ffu/ml

~ 108 ffu/ml

G1P4

CDC-9 strain

Jiang B et al, Vaccine 2008; Jiang B et al, HVI 2008

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwiuh976vOXOAhWC4SYKHSw_A-kQjRwIBw&url=http://www.coleparmer.com/Product/Corning_roller_bottle_850_cm2_easy_grip_cap/EW-01836-01&psig=AFQjCNH96cIDWnQZArSim18H7PVnMqaVVg&ust=1472520630684635

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwjOuvugveXOAhXEJiYKHdDaDcwQjRwIBw&url=http://www.sanisure.com/Products/Single-Use-Bioreactor-Accessory-Kits.aspx&psig=AFQjCNFB6B0uWQPnFf-uIUui0RFi6JkVoQ&ust=1472520710964413


IRV-CDC9 SHOWS IMMUNOGENICITY AND PROTECTION IN ANIMAL

MODELS

10

100

1000

10000

Wa G1P[8] MW333 G8P[4] WI61 G9P[8]

An

tib

od

ies (G

MT

)

pre dose 1

post dose 1

post dose 2

post dose 3

Induces cross-neutralizing-antibody to homotypic

and heterotypic strains IM route protects against oral challenge in

gnotobiotic piglets

Days of rotavirus shedding in stool after oral challenge (measured

by EIA)

Placebo IRV- CDC9

Jiang B, Wang Y, Glass RI. Human Vac & Immunotherap 2013; 9:1634-37; Wang Y, Azevedo M, Saif LJ et al Vaccine 2010; 28:5432-36

Wang Y, Vlasova A, Velasquez DE et al. PLoS One 2016; 11:e0166038


ONE DATA SLIDE OF UNPUBLISHED RESULTS OF CO-ADMINISTRATION OF IRV-CDC9 AND IPV IN RAT MODEL


IRV-CDC9 DEVELOPMENT: PROGRESS TO DATE AT SERUM INSTITUTE

Procurement of strains and related regulatory work completed.

Preparation and characterization of seed viruses completed.

Production procedure (pilot scale) standardized.

Inactivation kinetic study on pilot scale (one liter) completed.

Immunogenicity & cross protective immunity in animals established.

Assays validated, stability (up to 9 months) and potency completed.

Future plans

• Large scale production development process optimization (one year).

• Animal Toxicity materials preparation (six months).

• First in human study should start by Mid 2019

• Combination vaccine R&D – proposed with IPV

CONFIDENTIAL

Last updated: July 19, 2018

Tri

vale

nt

P2

-VP

8

PA

TH

/SK

Ch

em

ica

ls Multinational P2b/3 Futility/Efficacy Trial with active comparator for

prevention of severe RV gastroenteritis in healthy infants

cGMP

Manuf P3 Stand Alone

Vaccine

Value Proposition / Health

Economics of various options

Combination Vaccine

NRRV+ Penta/Hexa

Formulation

Feasibility cGMP Manuf Combination

Vaccine Formulation

Scale up

Immunization Schedule Clinical immunogenicity Trial- Prime (oral

RV vax) / Boost (trivalent P2-VP8)

IRV

CD

C9

CD

C/S

IIL

GLP Tox

cGMP

Manuf Ph1

Adult Phase 1

2024 20252018 2019 2020 2021 2022 2023

Clinical immunogenicity

bridging trial

IND

Ph2/3 Age De-escalation to

booster population

Proc Validation/cGMP

Manuf for Ph3

Ph3 booster extension study for efficacy

Local Registration

MFDS

WHO PQ

Local Registration

TBD

Licensure as a toddler booster

dose in ORV countries

Ph2: Immunogenicity Age

Descending

Proc Validation/CGMP Manuf P3

Ph3 clinical efficacy

Local Registration

MFDS

Traditional path

APPROXIMATE DEVELOPMENT TIMELINES FOR LEAD CANDIDATES



HIGH-LEVEL VALUE PROPOSITION OF NEXT GENERATION ROTAVIRUS

VACCINES

Strategic goal: To develop a parenterally administered alternative to currently available live attenuated oral rotavirus vaccines (LORVs) which is safe, provides increased relative efficacy and is more affordable to reduce the morbidity and mortality associated with severe rotavirus gastroenteritis (SRVGE) in infants and toddlers residing in low resource settings

THAT WILL (new benefits over existing alternative)

Increase relative vaccine efficacy over existing LORVs

Provide a parenteral route of administration to circumvent the purported mechanisms resulting in suboptimal efficacy of LORVs in infants and toddlers in low resource settings

Supply for public sector purchase at a lower price per dose and per regimen rotavirus vaccine than currently available LORVs

Has the potential to be co-formulated with other parenterally delivered pediatric combination vaccines to further reduce cost-of-goods sold (COGS), costs of vaccine delivery, and burden on the cold chain.

BECAUSE (Reasons to invest in product)

Immunization engenders antibody response that exerts protective effect at the gut level

Combining with EPI vaccines facilitates delivery and reduces associated costs

Enhanced efficacy and ease of administration, small footprint in cold chain, reduced vaccine wastage

Efficient, high throughput, low cost manufacturing platform. Greatly reduced supply constraints


TARGET PRODUCT PROFILES - NEW ROTAVIRUS VACCINES

Characteristic RotaVac

(Bharat Biotech)

BRV-PV Lyo (Serum Institute)

RV3-BB (PT Biofarma)

P2-VP8*-TV

(PATH / SK Vaccines)

IRV (CDC / Serum Institute)

Indication Prevention of severe rotavirus gastroenteritis

Target Population Infants Infants Infants and Neonates Infants Infants

Route of Administration Oral Oral Oral IM IM

Presentation / Formulation 5 dose vials (0.5mL/d) 1 or 2 dose vial

(2mL liquid)

1 dose vial (2mL liquid)

1 dose vial

Combo product with

penta or hexa

TBD

Combo product with

IPV

Dosing Schedule

3 doses (6, 10, 14wk DTP

schedule)


schedule)


schedule)

3 doses (6,10,14wk or 2,4,6mo)

3 doses (6, 10, 14wk DTP)

Duration of Protection 2 years 2 years 2 years 2 years 2 years

Vaccination Strategy Routine Routine Routine Routine + Penta Routine + IPV

Expected Efficacy 56% 36% - 67% 56 - 73% 75% (TBD) 75% (TBD)

Price per Dose $0.98 $1.70 (TBD) $1.17 (TBD) $0.85 (TBD) TBD

Licensure Date Q2 2014 Q4 2016 2020 2022 (TBD) 2024+ (TBD)

WHO PQ Date Q1 2018 Q4 2018 2022 2024 (TBD) 2025+ (TBD)

CONFIDENTIAL

Gavi prices:

Rotarix – $4.38/course

RotaTeq - $9.60/course


Variable Minimum Optimistic

Indication* Prevention of severe rotavirus gastroenteritis in infants and toddlers

Prevention of severe rotavirus gastroenteritis in infants and toddlers

Target Population* Individuals ~6 weeks to 2 years of age during primary EPI series (co-

administration)

Neonates through children 2 years of age during primary EPI series (co-

administration)

Target Countries GAVI-eligible and Lower-Middle Income Countries GAVI-eligible and Lower-Middle Income Countries

Efficacy* >75% >75%

Duration of Protection Through 2nd year of life Through 2nd year of life

Onset of Immunity 2 weeks after 3rd dose 2 weeks after 2nd dose

Indirect (Herd) Protection Yes Yes

Safety Clinically acceptable safety profile Clinically acceptable safety profile

Co-administration EPI series EPI series

Presentation Liquid formulated with Alum

Vaccine in presentations from one to five 0.5-ml doses filled in a “2R” vial

conforming to ISO 8362 dimensions. Vial height 3.5 cm

Liquid formulated with Alum

Vaccine in presentations from one to five 0.5-ml doses filled in a “2R” vial

conforming to ISO 8362 dimensions. Vial height 3.1 cm or less, for reasons of

volume reduction and dimensional harmonization.

Route of Administration and

dosing frequency

Intramuscular

3 doses at 3-8 week intervals, starting at 6 weeks of age

Intramuscular

2 doses at 3-8 week intervals, starting at birth

Vaccine Volume (cm3 /dose) 0.5ml/dose

17cm3

0.5 ml /dose

17cm3

Stability / Shelf Life 2 years at 2-8C ;VVM-30 (30 days @40C, >3 years at 2-8C) VVM-30 (30 days @40C, >3 years at 2-8C)

Product Registration Path Marketing Authorization Application from NRA designated as functional by WHO - Local license/WHO PQ

Marketing Authorization Application from NRA designated as functional by WHO - Local license/WHO PQ

WHO Prequalification Date 2023 2022

Primary Target Delivery Channel GAVI and Lower-Middle Income Countries GAVI and Lower-Middle Income Countries

Clinical Endpoint for Licensure Efficacy Efficacy

NEXT GENERATION INTERVENTION TARGET PRODUCT PROFILE

Last updated: July 19, 2018 © Bill & Melinda Gates Foundation | 24

COMBINATION OPTIONS – PREFERENCE UNDER DIFFERENT CONDITIONS

(A GATES FOUNDATION PERSPECTIVE)

Conditions where this combination would be preferred

Heptavalent vaccine

(Penta+IPV+NexGenRV)

Hexavalent-1 (Penta+IPV) &

NextGenRV

Hexavalent-2

(Penta+NextGenRV) & IPV

NextGenRV+IPV Combo &

Pentavalent

1

2

3

4

• Formulation for Heptavalent is feasible AND

• Price for Hepta is less than or equal to Hexa 1 plus NextGenRV

• Removal of IPV shot in combination with Penta makes space for

NextGenRV injection in the schedule, if efficacy can support

replacement of ORV

• Hexa1 exists but countries prefer to unbundle because Hexa1 price

is > Penta + 2 doses of IPV

• OR Hexa1 supply insufficient to cover demand in the 2023-2027

AND Hexa2 is ready in that time period

• OR After 2031, countries no longer want IPV

• Formulation and price are prohibitive in the options above

• 2 doses of NextGenRV provides sufficient protection

• OR an oral neonatal dose oral provides sufficient protection in

conjunction with the NextGenRV+IPV combo

Fo

rmu

latio

n fo

r H

ep

ta is n

ot fe

asib

le

CONFIDENTIAL

Clinical development

• Choice of comparator for Phase 3 efficacy studies – no correlate of protection identified

• Innovative immunization schedules and strategies – prime boost options

Manufacturing and formulation development

• Selection of manufacturing partner (requires a compelling business case)

• Stand-alone or combination vaccine strategies

• RV + pentavalent vaccine or hexavalent vaccine

• RV + IPV

Policy and introduction

• Policy and regulatory pathways need to be examined and developed

• PPC and gPPP required

Full Public Health Value Proposition


DEVELOPMENT CONSIDERATIONS

CONFIDENTIAL

Last updated: July 19, 2018

THANK YOU


SUBUNIT ROTAVIRUS VACCINE (VP6 INNER CAPSID PROTEIN)

Vaccine Expressed rotavirus proteins (based on rotavirus VP6 inner capsid)

Developer(s) Cincinnati Children’s Hospital Med Cent, USA Vaccine research center/University of Tampere Finland

Development VP6 expressed in E. coli as a fusion protein with maltose binding protein, and administered with attenuated heat-labile toxin LT (adjuvant). Animal studies: • Immunogenic (via CD4+ T cells) • Protected in challenge studies in mice Rotavirus VP6 - self-assemble into oligomeric structures (nanotubes, tubular and spherical structures) or produced using a Baculovirus expression system Animal studies: • Immunogenic, induce strong humoral and T cell immunity generated CD4+

CTLs with the potential to lyse RV-infected target cells. • Protective in small animal studies (predom. Homotypic)

Combined RV - norovirus vaccine candidate: Murine challenge: • showed protection against RV shedding observed regardless of delivery

route (intramuscularly, intranasally or a combination)

CONFIDENTIAL


SUBUNIT ROTAVIRUS VACCINE (VLP)

Vaccine Virus like particle approach

Developer(s) Mitsubishi Tanabe Pharma Co-op., Japan. Baylor College of Medicine, USA

Development

Rotavirus VP2, VP6, VP7 and NSP4 (from G1P[8] strains) Plant based production: VLPs are produced by transient expression in Nicotiana benthamiana plants using Agrobacterium vectors transfected with the rotavirus genes Animal studies: • induced the significant high level of anti-Wa IgG in dose dependent. • homologous neutralizing antibodies was statistically higher than the placebo

group

Various Constructs: VP2/VP4/VP6/VP7 VLP produced in baculovirus expression system.

Animal studies - murine

• Highly Immunogenic • Various delivery routes compared IM, IN and oral. • Parenterally or intranasally gave highest mean protection from challenge • Protective small animals (predominantly homotypic)

CONFIDENTIAL

NEXT GENERATION ROTAVIRUS VACCINES - WHO

Documents