The Challenge of Developing Vaccines for Global Health

Jerome H. Kim, MDInternational Vaccine Institute9th National Vaccine Conference20 Aug 2019

Overview

• Vaccines, Vaccination and Global Health• Access to Vaccines• Access as a function of the 3 critical junctures in

development• Suboptimal use:

‒ Rotavirus vaccine‒ Oral cholera vaccine

• Unused vaccine: Hepatitis E vaccine• No Vaccine: Vaccines for neglected diseases, Group A

Streptococcus• Summary

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Vaccines, Vaccination, and Global Health

Vaccines are cheap and cost effective

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For every $1 spent on vaccines, $16 are saved in future healthcare costs, lost income, and lost productivity. If all indirect costs are included, the ROI is 44:1 (Ozawa et al, Health Affairs, 2016).

Vaccines have a very high Return On Investment (ROI): 44 to 1

Developing Country Manufacturers Provide Quality & Value

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Vaccine Access: An analysis of barriers

Valley(s) of Death – barriers to access

7 Artwork by Erinn Acland, 2016

But: What about relative unknowns on the upstream side of basic research?

TRANSLATION IMPLEMENTATION

Rotavirus vaccine and the forgotten middle, or better late than never?

SUBOPTIMAL USE

Rota vaccine follows a traditional dissemination

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2006RotatecRotarix

app’d USA

2014RotaintroIndia

2010

2009WHO rec’dRota

2008 WHOestimates

450,000 deaths<U5

2015: 75 countries

introducedRota vaccine

2009Rota intro

intoRep S. Africa

2012MalawiGhana

Botswana

Gavi

Access turns a vaccine into successful vaccination

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Worldwide % Rotavirus 3 coverageWHO/UNICEF 2016

US NISCDC, 2015

2014

Middle income countries have been slow to incorporate rotavirus vaccine into national programs

11 Rota Council 18 June 2018

• 95 Countries have implemented rotavirus vaccine• 57% of children worldwide do not receive rotavirus vaccine• Less than 20% of Asian countries have implemented

rotavirus vaccination programs

Cost of rotavirus vaccines

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Source: Wikipedia Challenge: Remembering the forgotten middle: non-Gavi, non-high-income countries

The same gap has existed for other vaccines

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US DTP3 coverage 1980 96%

WHO, 2017

Demand - supply mismatch

SUBOPTIMAL USE

Demand – supply mismatch: oral cholera vaccine (OCV)

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• New source of supply in 2016• Increased demand, increased

supply, decreased disease = “virtuous cycle”

• WHO/UNICEF announce Ending Cholera 2030 Roadmap

WHO Weekly Epidemiologic Record, 2017

Challenge: For approved bacterial vaccines there remain imbalances in demand and supply that prevent necessary vaccines from being fully implemented.• Corollary 1: Regarding demand, are vaccines

properly valued? • Corollary 2: A race to the bottom (GH vaccine

price war) will hurt everyone.

Hepatitis E Vaccine: trapped in Acronymia – WHO PQ, SAGE, NRAs and NITAGs

Unused Vaccine

Hepatitis E

• Global burden of hepatitis E‒ 70,000 deaths (Rein et al, Hepatology 2012)‒ IHME: 26,100 (GBD, Lancet 2017)‒ WHO 2016: 56,000 (20,000,000 infections; 3,000,000 symptomatic cases)

• Large outbreaks superimposed on endemic disease‒ Recent outbreaks in Uganda, S. Sudan, Chad, Namibia‒ Endemic disease in Bengal, Bangladesh, Nepal

• Significant mortality in pregnancy‒ 20-25% mortality in 3d trimester of pregnancy

• Hepatitis E vaccines have significant efficacy‒ GSK-US Army study, Nepal (Shrestha et al, NEJM 2007): PP VE 95.6% at ~2

yr‒ Zhu et al, Lancet 2010; VE 100% at 12 mo‒ Zhang et al, NEJM 2015; VE 87% at 4.5 yr

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WHO (SAGE) position paper on Inovax hepatitis E vaccine

• Data on genotype 4 cross protection vs genotypes 1-3 is unknown• Data are insufficient for recommendation for routine use• Insufficient information for recommendation for use in children < 16, pregnant

women, chronic liver disease or travelers• Its use may be considered in epidemic outbreaks• Data gaps

‒ Information on safety‒ Epidemiologic data on burden, incidence, age specific attack rates, ‒ Cross protection ‒ Durability‒ Need for boosting

• Other requirements for prequalification‒ WHO technical reports series (TRS) for hepatitis E vaccines in preparation

▪ Guidance to NRAs and manufacturers on the 5 manufacturing processes, and on nonclinical and clinical aspects of recombinant hepatitis E vaccines to assure their quality, safety and efficacy

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Challenge: “Unincentivized” vaccines for HIV, TB, malaria, Group A Strep, Hepatitis E, invasive non-Typhoidal Salmonella need an alternative pathway for development, approval and implementation.

Unincentivized Vaccines, OR Vaccines for Neglected Tropical Diseases (and diseases that aren’t on the list of NTDs)

No Vaccine

Vaccine R&D: Work in progress?

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Newly Approved Vaccines

• 1/3 of R&D covers new vaccine targets• At least 32 diseases have no vaccines from

companies in review• Cost

▪ $500M less complex vaccine▪ $1 B more complex vaccine

• Failure rate▪ Only 7% of vaccines reaching preclinical

development are licensed▪ Hi Risk, no Incentive – why spend $1 B with a

high risk of failure and a low ROI if successful?

Diseases that don’t make the list of diseases without vaccine R&D• Group A Strep?• Hepatitis E?• Non typhoidal

Salmonella?• Shigella?

Diseases without vaccine R&D

Access to Vaccines Index 2017

21 G-finder Report, 2017

Work in Progress:Spending on Vaccine R&D, 2016

Existing vaccinesWHO, Global Vaccine Action Plan 2011-2020

HIVVaccines$724 M

TBVaccines$73 M

ShigellaVaccines$18 M

NTSvaccines$0.4 M

Schistovaccines$2.3 M

GASvaccines$1.2 M

Timely Access to Innovation: Concluding Remarks

Global health vaccines often impeded throughout value chain

• Access to vaccines that are also relevant for developed countries often fast-tracked in HICs

• However, access in LMICs can be significantly delayed or arrested due to post-licensure regulatory policy issues (e.g., WHO PQ)

• Even for candidates that have made it out of the lab and are somewhat less risky, further development unlikely unless funded by philanthropies and operational burden lies outside MNC

• As a result, candidates often "sit on the shelf" without getting developed

Discovery -Preclinical

Policy, Uptake

Clinical Development

Innovation Gap

Implementation Gap

Translation Gap

• Lack of market attractiveness dissuades biopharma from investing in the discovery of vaccinesfor diseases that mostly affect LMICs

• Weak pipeline as result

Challenge: The balance of incentive and risk dissuades big pharma from development of vaccines targeting low and middle income countries

Summary of Access Barriers

VALLEY OF DEATH 1

VALLEY OF DEATH 2

Unknown: little or no

work or vaccines

HILL BEFORE VALLEY OF DEATH 1

Summary

• Vaccine access is a critical deficiency, even for vaccines that are throughthe approval process.

• Access to vaccines may be impeded at several steps in a longdevelopment and implementation process.

• Vaccines for diseases of significant burden in HIC & LMIC are oftendeveloped for HIC populations and delays in access come in the transitionto other populations.

• There are vaccines that have had difficulty going through the process thatleads to PQ and WHO SAGE recommendation.

• Vaccines that target high burden diseases in MIC and LIC primarily areless common and examples of success and failure exist post efficacy hasbeen demonstrated.

• Developing vaccines of for infectious diseases found in LIC has beendifficult with gaps in knowledge and funding creating a poor pipeline forclinical development.

• Can the WHO Full Public Value of Vaccines help?

20 Years Advancing Global Health

Thank You!