Global Implementation of Rotavirus VaccinesProgress and Challenges

Umesh D. ParasharChief, Viral Gastroenteritis BranchCDC, Atlanta, USAuparashar@cdc.gov

TM

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Fourth Roger Glass Lecture

Scientific Program Committee

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Viral Gastroenteritis Team, CDC

Daniel Payne

Jackie Tate

Margaret CorteseJon Gentsch

Mike Bowen

Baoming Jiang

RotaTeq and Rotarix licensed in 2006

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•Large trials (~70,000 infants) in US, Europe, and South America

•No increased risk of intussusception

•85-98% efficacy against severe rotavirus disease

Vesikari et al and Ruiz-Palacios et al, NEJM 2006

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More than 90 countries have implemented national rotavirus vaccination programs

How well will vaccines performin routine use?

Will there be unanticipated benefits?

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106 107100

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107101

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2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

Hos

pita

lizat

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All-cause AGE Rotavirus

Impact on all-cause AGE and rotavirus-specific AGE hospitalizations in US children

Vaccine

Reduction in AGE hospitalizations in older unvaccinated children and adults in the US

Lopman et al. J Infect Dis 2011:204:980Gastanaduy et al JAMA 2013

Lopman et al. JID 2011

Pre-vaccine

Post-vaccine

Lower rates of hospitalization with rotavirus or unspecified gastroenteritis in vaccinated households in Persons 20-29 years Females 20-29 years (2008/2009) Males 30-39 years (2009/2010)

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Vaccinated children had ~20% reduction in risk of seizures requiring hospitalization or ED care compared with unvaccinated children during the year following vaccination

Reduced risk of childhood seizures associated with rotavirus vaccination (1)

Reduced risk of childhood seizures associated with rotavirus vaccination (2)

Compared to rotavirus-unvaccinated children, seizure risk reduced 24% (95% CI, 13% – 33%) in fully vaccinated 14% (95%CI, 0% – 26%) in partially vaccinated

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Analysis of 1.7 million children with 2950 seizures

Burke et al, CID, in press

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Num

ber o

f dia

rrhe

a de

aths

Month-Year

Age ≤11 months

Age 12-23 months

Age 24-59 months

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Vaccine Introduced(May 2007)

2008

2009

Richardson et al, NEJM 2010

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Diarrhea-associated mortality declined by 31% (95% CI, 1%-52%)

Vaccine effectiveness against diarrhea mortality 34% (95% CI, -28%-66%)

Lancet Global Health

Bar-Zeev et al, Lancet Global Health 2018

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How well will live oral rotavirus vaccines work in the developing world?

171 dot = 100 deaths

The vast majority of the ~200,000 annual deaths from rotavirus occur in developing countries

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Moderate efficacy seen in trials in low income African and Asian countries

Vaccine Region Countries Efficacy (95%CI)

RotaTeq Africa Ghana, Kenya, Mali 64% (40%-79%)

RotaTeq Asia Bangladesh, Vietnam 51% (13%-73%)

Rotarix Africa South Africa, Malawi 62% (44%-73%)

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19%20%

19% 19%

12% 13%

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2000

4000

6000

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10000

12000

2009 2010 2011 2012 2013 2014

% o

f Tot

al H

ospi

tal A

dmis

sion

s fro

m A

GE

Num

ber o

f Adm

issi

ons

Total Hospital Admissions AGE Admissions % of Admissions Due to AGE

VACCINE

Decline in proportion of childhood hospitalizations caused by diarrhea in Rwanda

Decline in rotavirus hospitalizations after vaccine implementation in Ghana

Armah et al CID 2016

50% RV+

26% RV+

28% RV+ 24%

RV+

Rotavirus vaccine introduction, April

2012

Rotavirus remains the leading cause of severe diarrhea in developing countries after rotavirus vaccine introduction

Cryptosporidium6%

Rotavirus55%Norovirus

5%

ETEC6%

Other28%

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Cryptosporidium

14%

Rotavirus22%

Norovirus12%ETEC

3%

Other49%

Before vaccine After vaccine

Plats Mills et al JID 2017

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How can we improve rotavirus vaccine performance in developing countries?

Multiple factors affect rotavirus vaccine efficacy

Poor response to

oral rotavirus vaccine

Transplacentaland breast milk

rotavirus antibodies

Nutrition

Gastrointestinal pathogens

Intestinal microbiota

Environmental enteropathy

Interference of OPV co-

administration

Withholding breastfeeding (~1 hr) at time of vaccine administration did not improve immune response

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Groome, 2014 (South Africa) Rongsen-Chandola, 2014 (India) Ali, 2015* (Pakistan)

Breastfeeding withheld Breastfeeding encouraged

Sero

conv

ersio

n %

Delaying 2-dose schedule or adding 3rd dose slightly improved vaccine response

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Ali, 2014 (Pakistan) Armah, 2016* (Ghana)

6 + 10 weeks 10 + 14 weeks 6 + 10 + 14 weeks

Sero

conv

ersio

n %

Supplementing with both Zn and probiotics slightly improved vaccine response

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No supplement Zinc alone Probiotic alone Zinc and probiotic

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Sero

conv

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RCT of 3 doses of RV3-BB given as either• Neonatal schedule (0-5 days, 8 weeks, 14 weeks)• Infant schedule (8 weeks, 14 weeks, 18 weeks)

Vaccine efficacy• 75% (95% CI, 7%-76%) for the neonatal schedule• 63% (95% CI, 34%-80%) for the infant schedule

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Booster rotavirus vaccine dose around 1 year of age?

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Booster rotavirus vaccine dose around 1 year of age?

Rotarix

RotaTeq

• No interference with concomitantly administered vaccines

• Increase in rotavirus antibody (IgA and IgG) in vaccinated children

Withdrawal of OPV should benefit rotavirus vaccines

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RV1+mOPV1 RV1+bOPV RV1+tOPV

Geo

met

ric m

eant

tite

r (G

MT)

RV-IgA geometric mean titer

p=0.037** p=0.010**

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20

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80

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RV1+mOPV1 RV1+bOPV RV1+tOPV

% s

eroc

onve

rsio

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RV-IgA seroconversion

p=0.035*p=0.035*

Emperador D et al. CID 2016

Concomitant OPV and rotavirus vaccine

Staggered OPV and rotavirus vaccine

Microbiome composition correlated with RV immunogenicity in Ghana

Harris et al, JID, 2017

34Kazi et al, JID, 2017

Histo-blood group antigens expressed on enterocytes are proposed receptors for rotaviruses

Seroconversion rates in Pakistani infants given Rotarix 19% among nonsecretors 30% among secretors with non-blood group O 51% among secretors with O blood group

Like polio – Injectable rotavirus vaccine?

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How well will vaccines protect against range of rotavirus strains?

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RotaTeq is pentavalent & Rotarix is monovalent

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G1 G3

G2 G4

P[8]

Five bovine-humanrotavirus strains

G1P[8]

Single human rotavirus strain

RotarixRotaTeq

Monovalent rotarix (G1P8) efficacy similar against vaccine & non-vaccine strains in Africa

59.759.155.270.9

51.556.964.4

83.879.264.1

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G1 G2 G3 G8 G9 G12 P[4] P[6] P[8] NonG1Rotavirus serotypes

Effic

acy

Steele et al. BMC Pediatrics

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Increase in G2P4 after implementation of monovalent Rotarix (G1P8) in Brazil

*Nakagomi et al, Arch Vir 153(3); 2008

*Gurgel et al, EID, 13(10), 2007

El SalvadorRotarix, 2006(opposite of Brazil)

Guatemala(no vaccine)

Honduras (no vaccine)

Patel et al. EID 2009

2005 2006 2007

P[8]G996%

P[8]G994%

P[8]G940%

P[4]G281%

P[4]G272%

P[4]G268%

P[8]G191%

P[8]G190%

P[8]G168%

Is increasing prevalence of G2P[4] in Brazil caused by vaccine pressure or is it just natural variation?

• Unique scenario with states using different rotavirus vaccines

• Decade prior to vaccine use, G1P[8] strains dominated nationally

• Decade after vaccine use•G12P[8] dominant in RotaTeq states•G3P[8] and G2P[4] in Rotarix states

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Will new rotavirus vaccinescause intussusception?

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Post-Licensure Intussusception Data

Low risk of intussusception found in several high and middle income countries (Mexico, US, Australia, UK)

~1-6 cases per 100,000 vaccinated

With both vaccines

RISKSBENEFITS

Benefits vs. Risks of Vaccination

Diarrhea Hospitalizations

(Deaths) Prevented

Intussusception Cases (Deaths)Caused

Mexico 11,600 (663) 41 (2)

Brazil 69,600 (640) 55 (3)

Australia 7,000 (0) 6 (0)

US 53,000 (16) 48 (0)

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No intussusception risk in large studyin 7 low income African countries!

46NEJM. April 2018

Who Will Supply Rotavirus Vaccineto the World?

Big Pharma

Merck

GSK

Emerging Manufactures

Brazil

Indonesia Germany

IndiaChina

ORAL ROTAVIRUS VACCINES WHO PQ

DCVMs include:Bharat SerumBioFarma HillemanPolyvac WuhanShanta ButantanLangzhou

Liquid presentationBharat Biotech

ROTAVACBharat Biotech

Live

-att

enua

ted,

ora

l Lamb rotavirusLanzhou Institute of Biological Products

Liquid BRV Serum Institute

Liquid BRVShantha Biotechnics

Human rotavirus Polyvac, Vietnam.

ROTASIILSerum Institute

RV3-BBBiofarma, Indonesia

Liquid BRV WUHAN China

Liquid BRV BUTANTAN Brazil

Discovery & preclinical Phase 2 Phase 3 MarketPhase 1

Live

-att

enua

ted

oral

(WHO

PQ

)

ROTATEQMerck

ROTARIXGSK

Heat stable pentavalentHilleman

MSD, India

Dormant Nationallicense

Slide: C Kirkwood & D Steele, BMGF

• 2 New Vaccines from India– Rotavac (WHO prequalified)– Rotasiil

• Prime Minister Modi “Government of India will provide a rotavirus vaccine to all Indian children”

India is taking the leadfor RV vaccines

Drug firms cut vaccine prices to the developing world*

United States PAHO GAVI / UNICEF

GSK $120 –$200/child

$15/child $5/child[up to 125 M doses;

over 5 yrs]

Merck $120 –$200/child

$15.45/child

$10.50/child[for volume over 30

M]

Bharat Biotech

– – ~ $3/ child

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• 3 doses/child: Merck, Bharat Biotech• 2 doses/child: GSK* Applies to GAVI tenders

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2006-2018Incredible years for new rotavirus vaccines!....

And great promise for the future!!