1. Accelerating Vaccine Introduction in Low-resource Countries
Kathleen M. Neuzil, MD, MPH
April 17, 2013
Photo credit: PATH

2. PATH transforms global health through innovation
Focus areas:
Health technologies
Vaccines and immunization
Maternal and child health
Reproductive health
Emerging and epidemic diseases
Emerging and epidemic diseases
PATH was founded in Seattle in 1977 as the Program for the Introduction and Adaptation of Contraceptive Technology.
We originally focused on international family planning and expanding access to modern methods of contraception. Our focus quickly expanded to include a variety of health tools and technologies.
The majority of PATH’s funding comes from foundations, including the Bill & Melinda Gates Foundation, and the US government, particularly the Agency for International Development; however, we also receive funding from international organizations (e.g., GAVI), non-US governments, and individual contributors. Our annual budget is nearly $300 million.
Photo: PATH/Mike Wang

3. PATH’s work in vaccines and immunization
Vaccines & Immunization
Other PATH Work
RANGE OF ACTIVITIES
Increasing availability of existing vaccines.
Closing the gap in uptake of newly available vaccines.
Developing technology in support of vaccines and immunization.
Working with partners to develop new vaccines.
Comprehensive approach encompassing research and development, advocacy, financing, distribution, administration, and uptake.
PATH’s work in vaccines and immunization makes up approximately 34% of our work.
April 17, 2013

4. Overview Discuss public health impact of vaccines.
Highlight discrepancies between vaccine use in developed and developing world.
Case studies of new vaccine introduction in the developing world.
April 17, 2013

5. Focus on major disease threats
                                                                                                                               
Focus on major disease threats
Major causes of death
in children under age five
1.5 million children die from vaccine-preventable diseases each year.
Pneumonia and diarrhea are two leading causes of death among children under the age of five in the developing world.
[NOTE: This slide requires three “clicks” to view the entire slide.]
The percentage of mortality due to diarrhea and pneumonia are actually higher than 11% and 14% respectively. Of the 40% of child deaths due to neonatal causes, 1% of these are from diarrhea and 4% are from pneumonia.
Source: L Liu, Johnson HL, Cousens S, et al. Global, Regional, and National Causes of Child Mortality: An Updated Systematic Analysis for 2010 with Time Trends Since The Lancet. 2012;379(9832):
April 17, 2013

6. Rotavirus vaccine program
Photo: PATH/Mike Wang

7. The Rotavirus Vaccine Program
A public/private global health partnership launched in 2000 to improve access to immunization for children in impoverished countries.
PATH Rotavirus Vaccine Program
Accelerated Development and Introduction Plan (ADIP) established with generous grant from GAVI Alliance.
Partnership with WHO and US CDC.
Mission: To reduce child mortality and morbidity from diarrheal disease by accelerating the availability of rotavirus vaccines appropriate for use in developing countries.
So, who are the players?
GAVI = Donor
PATH RVP = Recipient, Collaboration with CDC and WHO
First, there was an awareness that rotavirus was a problem, we had potential solutions in vaccines that would soon be coming to market, so grant was given with goal of accelerating availability of rota vaccines……Historically, a 15 to 20 year gap between availability of vaccine in developed world and developing world—goal to reduce that gap;
Eligibile GAVI countries:
<$1,000 Gross National Income per capita
72 countries
Raised $3.6 billion in traditional funding; additional $4 billion from alternative financing mechanisms
April 17, 2013

8. Rotavirus is the most common cause of severe, dehydrating diarrhea among children worldwide
Each year it causes:
25 million outpatient visits
2 million hospitalizations
Over 450,000 deaths
Global surveillance shows that 40% of diarrheal hospitalizations are due to rotavirus
Slide 8
April 17, 2013

9. Low-resource countries in Asia and Africa carry the greatest rotavirus disease burden
Global annual rotavirus deaths: 450,000— predominantly in developing countries
Under-five deaths attributable to rotavirus
The Asian Rotavirus Surveillance Network found that nearly half of all children hospitalized for diarrhea had rotavirus.
In Africa, up to 40 percent of children hospitalized with acute diarrheal illness are infected with rotavirus.
In South Africa, more than 75 percent of children will contract rotavirus before their first birthdays.
Map: WHO. New and underutilized vaccine implementation: rotavirus website. Accessed 26 March 09.
April 17, 2013

10. Two highly effective rotavirus vaccines
Rotarix®
(GSK Bio)
RotaTeq®
(Merck & Co)
Origin
Human monovalent
Bovine pentavalent
Strain
G1, P[8]
G1, G2, G3, G4, P[8] & G6P[7]
Vaccine course
2 doses - oral
3 doses - oral
Pivotal Phase III trial
n=63,225 (20,169 for efficacy) Latin America and Finland
n=70,301 (5,673 for efficacy) Latin America, US and Finland
Efficacy vs rotavirus GE
85% - 100% vs severe rota gastroenteritis
98% vs severe rota gastroenteritis
Intussusception risk
No association observed in clinical trials
Ruiz-Palacios GM. NEJM 2006; 543: Vesikari T. NEJM 2006;354:23-33.
April 17, 2013

11. Clinical studies required in low-resource countries of Africa and Asia
WHO advisory group recommended “inclusion of rotavirus vaccination into the national immunization programmes of regions and countries where vaccine efficacy data suggest a significant public health impact…”
Because of concerns that “live oral vaccines may not be fully effective in protecting the poorest children in developing countries,” SAGE noted “the need for urgently generating efficacy data in Asia and Africa, where the disease burden is very high.”
WHO. Wkly Epidemiol Rec 2006; 82: 1-12.
April 17, 2013

12. Goal: Design and execute clinical trials that will inform policy
Which vaccine?
Where? Are the populations broadly representative?
Who? Are the participants broadly representative?
Efficacy or effectiveness?
Outcome measure?
Logistical considerations
Slide 12
April 17, 2013

13. Rotavirus vaccine study sites
Mali
Ghana
Kenya
GSK-RVP partnership
Merck-RVP partnership
Malawi
South Africa
April 17, 2013

14. Clinical trials of rotavirus vaccines in low-resource settings in Africa and Asia
: Three RCT, over 12,000 children at sites in seven countries
9th International Rotavirus Symposium, Johannesburg, SA, August 2010
Source: WHO Statistical Information System (WHOSIS)
April 17, 2013

15. GSK-RVP Phase III randomized, controlled efficacy trial in Africa (Malawi and South Africa)
Treatment group
Dose1 (6 wks)
Dose2 (10 wks)
Dose3 (14 wks)
3 doses
RotarixTM
2 doses
placebo
Placebo
Routine EPI vaccines, including oral polio vaccine (OPV), co-administered
HIV-positive infants not excluded
Breastfeeding not restricted
Focused on severe disease
Madhi SA, Cunliffe NA, Steele AD et al. NEJM 2010; 362:
Slide 15
April 17, 2013

16. Primary Outcome
Infants with at least one episode of severe rotavirus gastroenteritis during the period from 2 weeks post-last dose until one year of age were counted as the primary outcome in the Rotarix-pooled and placebo groups.
Severe Rotavirus GE
Pooled Vaccine
Placebo
Efficacy (%)
95% CI
# Cases %
# Cases 56
1.9 70
4.9
61.2
44, 73
Madhi SA, Cunliffe NA, Steele AD et al. NEJM 2010; 362:
Slide 16
April 17, 2013

17. Efficacy and severe rotavirus GE episodes prevented per 100 children, overall and by country
61.2%
76.9%
49.5%
(44.0 – 73.2)
(56.0 – 88.5)
(19.2 – 68.3)
Slide 17
April 17, 2013

18. Efficacy against severe rotavirus gastroenteritis in the first year of life
Region
Vaccine
Countries VE
95% CI
Africa
RotarixTM
Malawi, South Africa
61.7
44.0, 73.2
RotaTeq®
Ghana, Kenya, Mali
64.2
40.2, 79.4
Asia
Bangladesh, Vietnam
51.0
12.8, 73.3
Madhi SA, Cunliffe NA, Steele AD et al. NEJM 2010; 362:
Zaman K, Anh DD, Victor JC et al. Lancet 2010; 376:
Armah GE, Sow S, Breiman RF et al. Lancet 2010; 354:
Slide 18
April 17, 2013

19. Translating efficacy into population impact
1.7 million lives saved
Atherly DE, Dreibelbis R, Parashar UD et al. J Infect Dis 2009; 200: S28-38.
April 17, 2013 19

20. Richardson et al, NEJM 2011
April 17, 2013

21. United States: Reduction in gastroenteritis hospitalizations among children too young or too old to be vaccinated
Curns AT et al. JID 2010; 201: 1617.
April 17, 2013

22. From 2000 through 2009: Over 5 million children died from rotavirus disease
Under-five deaths attributable to rotavirus
The Asian Rotavirus Surveillance Network found that nearly half of all children hospitalized for diarrhea had rotavirus.
In Africa, up to 40 percent of children hospitalized with acute diarrheal illness are infected with rotavirus.
In South Africa, more than 75 percent of children will contract rotavirus before their first birthdays.
Global annual rotavirus deaths: 527,000— predominantly in developing countries
Map: WHO. New and underutilized vaccine implementation: rotavirus website. Accessed 26 March 09.
Global mortality figure: WHO. Weekly Epidemiological Record. 82(32).
April 17, 2013

23. National RV introductions by geographic region: 42 countries*
Europe
Armenia
Austria
Belgium
Finland
Israel
Luxembourg
Moldova
Asia
Philippines
Americas
Bolivia
Brazil
Cayman Islands
Colombia
Dominican Republic
Ecuador
El Salvador
Guatemala
Guyana
Honduras
Mexico
Nicaragua
Panama
Paraguay
Peru
United States
Venezuela
Middle East
Bahrain
Iraq
Qatar
Yemen
Africa
Botswana
Ghana
Malawi
Morocco
Rwanda
South Africa
Republic of Sudan
Tanzania
Western Pacific
Australia
Fiji
Marshall Islands
Micronesia
Palau
*National introductions by geographic region, as of 5 Dec 2012
RV = rotavirus vaccine
Not GAVI-eligible
[30]
GAVI-eligible
[12]
April 17, 2013

24. Meningitis (Men A) vaccine project
Slide 24
PATH/Gabe Bienczycki

25. PATH Meningitis (Men A) Vaccine Project (MVP)
Background
Created in June 2001 by a grant from the Bill & Melinda Gates Foundation as a 10-year partnership between WHO and PATH. Dr. F. Marc LaForce (PATH) selected as Project Director.
Goal
Eliminate epidemic meningitis as a public health problem in Sub-Saharan Africa through the development, testing, licensure, and widespread use of meningococcal conjugate vaccines.
April 17, 2013 25

26. Epidemic meningitis in Africa10
20,000
40,000
60,000
80,000
140,000
170,000
200,000 50 60 70 80 90 96
92,347
80,743
88,939
250,000+
Number of cases 01
100,000
88,199
68,089
Meningitis belt: extends from Ethiopia to Senegal: Sudan, Ethiopia, Chad, Niger, Northern Nigeria, Burkina Faso, Mali are considered hyper-endemic
1905: first documented epidemic, Northern Nigeria
: second cycle with over 45,000 deaths in Northern Nigeria
: third cycle: Nigeria 6456 deaths
: 340,000 cases with 53,000 deaths
: 300,000 cases with 30,000 deaths
2010: 30,103
Map source:
April 17, 2013

27. MVP Men A vaccine development: Early activities
Met with public health authorities in Africa.
Understand constraints of new vaccine introduction.
Price a high obstacle (must be less than USD $0.50 per dose to be sustainable).
Approached multinational vaccine companies.
No interest in developing a product with such a low price.
April 17, 2013 27

28. MVP Men A vaccine development model
GSK also builds relationships with local partners and can grow market share in developing countries.
April 17, 2013 28

29. Case: Men A conjugate vaccine
Partnership terms
PATH provides IP (conjugate technology), technical consultants/expertise, and clinical development funding.
Serum Institute of India, Ltd. (SIIL) to supply guaranteed volume vaccine per year for at least 20 years. Vaccine price at launch USD <$0.50/dose.
WHO to lead vaccine introduction activities in sub-Saharan Africa.
April 17, 2013 29

30. MenAfriVac™ development highlights
Conjugation, process development, process optimization, quality control, batch size scale-up at SIIL assisted by a phalanx of highly experienced technical consultants.
Clinical trials [from 2005 to 2010 for use in individuals from 1 to 29 years of age; from 2008 to 2013 (proposed) for use in children <1 year of age].
First in India, then sub-Saharan Africa.
Well tolerated, robustly immunogenic in approximately 7,000 subjects across seven clinical trials.
Yaoundé Declaration (2008)—African health ministers commit to vaccinate 320 million individuals from 1 to 29 years of age and 25 million infants (birth cohort) across 26 countries by
April 17, 2013 30

31. MenAfriVac™ licensure and introduction highlights
Marketing Authorization India, January 2010.
WHO Prequalification, June 2010.
SIIL manufacturing capacity approximately 50 million doses/year.
Pilot vaccination campaigns (September to December 2010) in Burkina Faso, Mali, Niger (1.2 million vaccinees).
Country-wide vaccinations 2010: approximately 19.5 million vaccinated prior to 2011 meningitis season.
2011, 2012: Approximately 110 million (total) vaccinated prior to 2013 meningitis season.
April 17, 2013 31

32. Launching of MenAfriVac campaign in Burkina Faso
World Health Organization
24 September 2017
MenAfriVac introduction in Burkina Faso
Launching of MenAfriVac campaign in Burkina Faso
06/12/2010
April 17, 2013 32

33. April 17, 2013

34. World Health Organization
24 September, 2017
24 September, 2017
24 September, 2017
Impact of MenAfriVac vaccination on carriage of NmA in Burkina Faso
Kristiansen PA, Diomandé FVK, Ba AK, et al. Impact of the serogroup A meningococcal conjugate vaccine, MenAfriVac, on carriage and herd immunity. Clinical Infect Dis Published Online October 19, doi: /cid/cis892.
April 17, 2013 34 34

36. Key points: Accelerating vaccine introduction in the developing world
Childhood vaccine-preventable disease levels are at or near record lows.
Significant disparities exist between vaccine use in the industrialized and developing countries.
Health system and financing issues are major barriers to accelerating vaccine use in developing countries.
Political will is critical to overcoming these barriers.
April 17, 2013