Rotavirus vaccines
Contentious issues and the way
forward
Conflict of interest
• Work on rotavirus infection and vaccination in my
group is supported by the WHO, European
Commission, ICMR, DBT, PATH and the Bill and Melinda
Gates Foundation
• We serve as the clinical laboratory for Phase II studies
by Shantha Biotech and Serum Institute of India
• We are conducting a phase III study for Bharat Biotech
India Ltd (Financial support from DBT and PATH)
• We will test samples from the phase III study for Serum
Institute of India (Financial support from PATH)
Key questions
• Will the current vaccines work as well in India
as elsewhere?
• Which vaccine is better?
• What is the risk of intussusception?
• Will strain replacement take place?
• Is there a need for the vaccine in the universal
immunization program?
• Is the age restriction necessary?
Will the current vaccines work as well
in India as elsewhere?
What’s driving the rapid roll out of
rotavirus vaccines?
Figure 1. Number of Diarrhea-Related Deaths among Children 59 Months of Age
or Younger from July 2002 through May 2009 in Mexico, According to Age Group.
Vaccine
coverage
and
rotavirus
disease in
6
countries
Impact on hospitalizations and costs
• In the USA, nationally, for the 2007-2009
period, there was an estimated reduction of
64,855 hospitalizations, saving approximately
$278 million in treatment costs
Cortes et al, NEJM, 2011
Africa
• Rotarix
– 4417 infants in per-protocol efficacy analysis
– Pooled vaccine efficacy, 61.2%; 95% CI, 44.0 to 73.2%.
– Vaccine efficacy lower in Malawi than in South Africa
(49.4% vs. 76.9%);
– Number of episodes of severe rotavirus
gastroenteritis that were prevented was greater in
Malawi than in South Africa (6.7 vs. 4.2 cases
prevented per 100 infants vaccinated per year).
Madhi et al, NEJM, 2010
Africa
• Rotateq
– 5468 infants
– Pooled vaccine efficacy, 39.3%; 95% CI, 19.1 to
754.7%.
– Vaccine efficacy lower in Mali than in Ghana or
Kenya
– Vaccine efficacy lower in second season than first
– IgA seroresponses 73-82%
Armah et al, Lancet, 2010
Asia
• Rotateq
– 2036 infants
– Vaccine efficacy 48.3% (95% CI 22.3–66.1) against
severe disease
Zaman et al, Lancet, 2010
So what should we expect in India?
• No vaccine efficacy data as yet
• Immunogenicity data from a phase II study with 116E
vaccine showed 89% IgA seroresponse
• Efficacy studies for 116E have completed enrollment
and are ongoing
Bhandari et al, J Infect Dis, 2009
Key data on protective immunity from Mexico
studying natural infections
33 (22 - 42)
2 Subsequent
infections are less
severe
3 Second infections
1 Complete protection from moderate
to severe gastroenteritis after 2
infections
were more likely to
be caused by another G
type (P0.054)
Velazquez et al,
NEJM 1996
Protection against rotavirus diarrhoea
Outcome and no.
of previous
infections
No. of
episodes
Incidence per 100
child months
371
13.81
1
338
8.5
2
236
6.7
3
100
4.68
0
84
3.13
1
70
1.76
2
32
0.91
3
15
0.70
Unadjusted relative risk
(95% CI)
Adjusted efficacy
(95% CI)
Any infection
0
0.62 (0.53 – 0.71)
0.49 (0.41 – 0.57)
0.34 (0.27 – 0.42)
39 (29 – 47)
52 (43 – 59)
67 (59 – 74)
Mild diarrhoea
0.56 (0.41 – 0.77)
0.29 (0.19 – 0.44)
0.23 (0.13 – 0.39)
44 (23 – 59)
72 (58 – 81)
79 (64 – 88)
Moderate to severe diarrhoea
0
17
0.63
1
21
0.53
2
10
0.28
3
3
0.14
0.83 (0.44 – 1.58)
0.45 (0.21 – 0.98)
0.22 (0.07 – 0.76)
18 (-57 – 57)
57 (6 - 80)
79 (29 -94)
Comparison of severity
between orders of
rotaviral infection
Comparison of Mexican & Vellore cohorts
Mexico
Vellore
No. of children recruited &
completing follow up
200 (77% follow up)
452 (373 with 99.5% follow
up)
Frequency of visits and stool
1/week, 1/week + diarrhoea
2/week, 1 in 2 weeks +
diarrhoea
Infections identified
316, 57% stool and 77%
serology
1103, 48% stool and 76%
serology
Order of infection
52% first infections, 48%
subsequent
30% first infections, 70%
subsequent
Time to infection
34% infected by 6 mo
53% infected by 6 mo
Symptoms in 1st infection
47%
30%
Severity
No child had moderate to
severe diarrhoea after 2
infections
22.4% of 3rd or later rotavirus
diarrhoea were moderate or
severe
Velazquez et al, NEJM, 1996
Gladstone et al, NEJM, 2011
Modeling the impact of vaccination
given current data
1
Vaccine impact (1-relative incidence)
0.9
>>High income incidence
>>Middle income incidence
>>Mid/high income natural protection
0.8
0.7
0.6
>>High income immunogenicity
>>Middle income immunogenicity
0.5
>>90% coverage
0.4
Baseline (Low income, 70% coverge)
0.3
0.2
0.1
0
Lopman et al, PloSOne 2012
0
1
2
3
4
Years since start of vaccination program
Which vaccine is better?
Licensed oral rotavirus vaccines
• Rotarix ® (GSK) live, oral,
monovalent, human P[8]G1,
attenuated by serial passage in cell
culture
• Two dose schedule along with
EPI/routine childhood vaccinations
• 85% efficacy against severe
rotavirus disease and
hospitalizations (two dose
schedule, 6 and 10 weeks)
Ruiz-Palacios et al, NEJM, 2006
Licensed oral rotavirus vaccines
• Rotateq ™ (Merck) live, oral,
human-bovine reassortant (P[8],
G1, G2, G3, G4)
• Three dose schedule with
EPI/routine childhood
vaccinations
• 74% and 98% efficacy against all
and severe rotavirus disease
Vesikari et al, NEJM, 2006
Comparison of Rotarix and Rotateq
Angel et al, Nat Rev Microbiol, 2007
Type specific protection in developing
countries
Study
Vaccine
G1
protective
efficacy
P
Value
Non-G1
protective
efficacy
P Value
Ref
Africa
Rotarix
64.1
(29.9–82.0)
0.002
59.7
(37.1–74.4)
<0.001
Africa
Rotateq
32.3
(–1.8 - 55.4)
27.1—87.5
Asia
Rotateq
46.2
(–13.5-75.7)
29.1-67.2
Madhi et
al, NEJM
2010
Armah et
al, Lancet
2010
Zaman et
al, Lancet
2010
Serum neutralizing antibodies with
Rotateq in Asia
Serum
neutrailizing
antibody to
G1
G2
G3
G4
P8
Vaccinee Placebo
Vaccinee
GMT
Placebo
GMT
32.1
9.9
2.3
0.8
99.5
23.0
19.9
12.5
28.2
18.3
27.5
3.0
0
5.3
30.8
51.4
78.9
10.1
15.1
18.0
Serum IgA responses were seen in 87.8% of vaccinees and 18.2% of controls
Zaman et al, Lancet, 2010
What is the risk of intussusception?
Intussusception and the first licensed vaccine
• Tetravalent human-rhesus reassortant
rotavirus vaccine (RRV-TV) developed at
NIH
• Manufactured by Wyeth, licensed in
1998 as Rotashield®
• 1.5 million doses given
• Vaccine Adverse Events Reporting System
identified possible association with
intussusception
• Withdrawn by the company in 1999
Intussusception in vaccine trials
• Rotashield was calculated to have a risk of one
excess intussusception per 10,000 vaccinees
• The Rotateq and Rotarix trials had nearly
70,000 children each in the safety studies
• No increased risk found, but companies asked
to report intussusception for the first 3 years
after licensure by the Federal Drug
Administration in the US
Post-marketing surveillance
• Mexico 2008-2010, attributable risk of 3 to 4 additional cases of
intussusception per 100,000 vaccinated infants (Velazquez et al, Ped
Infect Dis J, 2012)
• US 2000-2009, Compared with 2000-2005, the rate was greater in
2007 (rate ratio [RR], 1.10), similar in 2008 (RR, 0.95), and lower in
2009 (RR, 0.93) (Yen et al, J Infect Dis, 2012)
• US 2006-2010, no increased risk (Shui et al, JAMA, 2012)
• US 1997-2009, no increased risk (Zickafoose et al, Arch Pediatr
Adolesc Med, 2012)
• US 2006-2008, no increased risk (Loughlin et al, Ped Infect Dis J,
2012)
• Mexico and Brazil, short-term risk of intussusception in
approximately 1 of every 51,000 to 68,000 vaccinated infants (Patel et
al, NEJM, 2011)
• Australia, no overall increase in intussusception following receipt of
rotavirus vaccine, there was some evidence of an elevated risk
following the first dose of both vaccines (Buttery et al, Vaccine 2011)
• US, 2006-2008, no increased risk (Belongia et al, Ped Infect Dis J
2010)
Will strain replacement take place?
Strain replacement
• Two reports of disappearance of G1 strains
and replacement with G2P4 strains in Brazil
after introduction of nationwide introduction
of rotavirus vaccine
• Gurgel et al, Emerg Infect Dis 2007, Nakagomi et al,
Arch Virol 2008
Strain reassortment
• Vaccine or vaccine-reassortant rotavirus
strains detected in 5 (4.7%) of 106
immunocompetent children who required
treatment for rotavirus gastroenteritis at a
large pediatric hospital in Texas in 2009-2010.
• Four strains were related to pentavalent
rotavirus vaccine while one was related to
monovalent rotavirus vaccine.
Boom et al, J Infect Dis 2012
• Is there a need for the vaccine in the universal
immunization program?
• Is the age restriction necessary?
Country level vaccine efficacy against severe rotavirus
diarrhea incidence and 2009 under five mortality
Fischer Walker and Black, BMC Public Health, 2011
Public health implications
Fischer Walker and Black, BMC Public Health, 2011
Public health impact
• Rotavirus vaccine prevented severe rotavirus episodes in all
regions; 81% of episodes in Latin America, 42.7% of
episodes in high-mortality Asia, 50% of episodes in subSaharan Africa, 88% of episodes low-mortality Asia and
North Africa, and 91% of episodes in developed countries
• Although vaccine efficacy is lower, impact on severe disease
and mortality is high because of the high incidence
• Higher vaccine efficacy is desirable but should not delay use
of an effective public health tool
Thank you