Kim Mulholland Murdoch Childrens Research Institute, Melbourne - - PowerPoint PPT Presentation

Kim Mulholland Murdoch Childrens Research Institute, Melbourne London School of Hygiene and Tropical Medicine University of Melbourne Department of Paediatrics

› New vaccines –

– Global - HPV, PCV, Rotavirus, RSV, – LMICs - Dengue, typhoid, malaria

› Measles › Vaccine development and evaluation › Equity and vaccines

› All three current vaccines are similarly effective against cancer

– Minimal incremental benefits of new vaccines

› Price and supply are the major issues

– HPV2 (Cervarix) production to increase in 2021/2 – New producers coming online eg. SII HPV4

› Ideal vaccination schedules unclear

– Younger children – Single dose strategy would be a major advance

› Integration with screening and treatment for CaCx › Who to vaccinate:

– All males – Older women – HIV+ – Sex workers – MSM

› All three current vaccines are similarly effective against cancer

– Minimal incremental benefits of new vaccines

› Price and supply are the major issues

– HPV2 (Cervarix) production to increase in 2021/2 – New producers coming online eg. SII HPV4

› Ideal vaccination schedules unclear

– Younger children – Single dose strategy would be a major advance

› Integration with screening and treatment for CaCx › Who to vaccinate:

– All males – Older women – HIV+ – Sex workers – MSM

› Vaccine price – after 20 years of PCV › Serotype replacement may emerge

– No clear monitoring system in place

› Increasing valency:

– Pfizer – PCV24 or more – GSK – stick with PCV10

› Reaching the highest risk is the challenge

› Early vaccine trials enhanced disease › Monoclonal Ab available since 2003 (palivizumab)

– Very expensive; monthly injections during RSV season – Off patent now

› Long-acting mAb in trials (Astra Zeneca/Sanofi)

– Effective, but very expensive

› Maternal vaccination (Novavax)

– 4636 subjects; 87 sites; 11 countries – Results uninterpretable

› Infant vaccines in early trials

› WHO prequalified vaccines

– Rotarix (GSK) – 2 dose – Rotateq Merck) – Rotavac (Bharat) – Rotasil (Serum Institute of India)

› Why is Rotavirus vaccine not used in Asia? › Intussusception

– Very common in east Asia – Very low incidence with existing vaccines

› New producers

– Neonatal strains – Rotavin

› 0,8,14 weeks (neonatal, n=498) › 8,14,18 weeks (infant, n=511) › Vaccine efficacy 0 - 18mths

– Neonatal – 75% (41-91) – Infant – 51% (7-76)

› Human neonatal strain NEJM 2018; 378:719-30

› Dengue fever › Typhoid › Malaria

Sanofi – Dengvaxia (33 sites) Takeda (28 sites) Butantan (15 sites)

From MG Guzman, 2017

“Dengvaxia might increase the risk of severe disease in people who had never been exposed to the virus. The news prompted an uproar in the Philippines, where more than 800,000 school-age children had been vaccinated in 2016.”

Philippines Health Under- Secretary Enrique Domingo, BBC February 3rd 2018

“Dengvaxia might increase the risk of severe disease in people who had never been exposed to the virus. The news prompted an uproar in the Philippines, where more than 800,000 school-age children had been vaccinated in 2016.”

Philippines Health Under- Secretary Enrique Domingo, BBC February 3rd 2018

› Information

– Education – medical staff, journalists, general community – National quality web sites – Vigilant management of crises

› Role of industry

– Big pharma are not trusted by many (including doctors) – Big pharma have profited from some safety scares

› Why are major phase 3 trials now controlled by industry?

– Poorer quality; too many sites – Much more costly (CRO costs – Quintiles, etc) – Results often not trusted

› Information

– Education – medical staff, journalists, general community – National quality web sites – Vigilant management of crises

› Role of industry

– Big pharma are not trusted by many (including doctors) – Big pharma have profited from some safety scares

› Why are major phase 3 trials now controlled by industry?

– Poorer quality; too many sites – Much more costly (CRO costs – Quintiles, etc) – Results often not trusted

Quintiles CEO Tom Pike Salary $9.5 million/year + $7 million stock

› Huge increase in support for typhoid vaccines

– WHO, Gavi support for TCVs

› Better Ab levels than Vi vaccine

– uncertain anamnestic responses

› TyVAC Consortium trials

– Bangladesh, Nepal – only 2 years followup (Nepal VE 80-90%) – Malawi – 2-3 years followup

› Future depends on medium-long term efficacy › Pakistan introducing TCVs › Antimicrobial resistance likely to be major driver

› CSP – targets the sporozoite › Hepatitis B surface antigen › Efficacy against clinical malaria in 5-17 mths age - 39% › European Medicines Agency (EMA) – “positive opinion” › But:

– Possible safety signals – meningitis, female mortality – Feasibility of schedule

› Current status – phased introduction into areas in Ghana, Malawi, Kenya

RTS,S/AS01

2015-01 2015-02 2015-03 2015-04 2015-05 2015-06 2015-07 2015-08 2015-09 2015-10 2015-11 2015-12 2016-01 2016-02 2016-03 2016-04 2016-05 2016-06 2016-07 2016-08 2016-09 2016-10 2016-11 2016-12 2017-01 2017-02 2017-03 2017-04 2017-05 2017-06 2017-07 2017-08 2017-09 2017-10 2017-11 2017-12 2018-01 2018-02 2018-03 2018-04 2018-05 2018-06 2018-07 2018-08 2018-09 2018-10 2018-11 2018-12 2019-01 2019-02 2019-03 2019-04 2019-05 2019-06 2019-07 2019-08

5000 10000 15000 20000 25000 30000 35000 40000 45000 50000 55000 60000 65000 70000 75000 80000 85000 90000 95000 1e+05 Month of onset Measles cases (Lab+Epi+Clinical)

AFR AMR EMR EUR SEAR WPR

Source: WHO

5000 10000 15000

<1 year 1-4 years 5-9 years 10-14 years 15-24 years 25-39 years 40+ years

0 doses 1 dose 2+ doses Unknown

Age at onset

Number of cases

Philippines age distribution, vaccination status, and incidence, 2018-07 to 2019-06

1000 2000 3000 4000 5000 6000 7000

Incidence rate per 1,000,000

6549.7 1423.5 269.6 149.1 372.6 235.2 27.1

477 deaths in 1st 4 months of 2019 (UNICEF data)

› Decline in vaccine uptake – global?

– Isolated groups unvaccinated – General increase in vaccine hesitancy? – General decline in respect for science?

› Measles is the indicator of a larger problem › Why is there so little research in the field?

– What research is needed?

• 1. What are the causes of outbreaks in settings with high

vaccine coverage?

• 2. Develop better point of care diagnostics
• 3. What are the best strategies for increasing coverage of

the first dose of measles vaccine at 9 or 12 months?

• 4. What are the best strategies for increasing coverage of

the second dose of measles after12 months?

• 5. How can communities be engaged in planning,

implementing and monitoring health services?

• 6. What capacity building is needed for health workers?

JL Kriss et al, Vaccine 2019

› Move away from national average data:

– Find out who the unvaccinated are – Find out who the measles cases and deaths are

› Experiment with measles schedules › Discuss the need for a new generation of vaccines › Above all, question that status quo, which is clearly failing

› Move away from national average data:

– Find out who the unvaccinated are – Find out who the measles cases and deaths are

› Experiment with measles schedules › Discuss the need for a new generation of vaccines › Above all, question that status quo, which is clearly failing

• Universal Childhood

Immunization (UCI)

• National and global

data

1980s

• Millenium

Development Goals (MDGs)

• National and global

data

2000-15

• Identify and reach

the unvaccinated

• Highest risk:
• Emergency settings
• Marginalized

communities

current

• 1. Equity

– Universal access to life saving vaccines = equity – Who is excluded from national programmes?

› Poor, marginalized communities › Minority communities › Refugee and internally displaced children

• 1. Equity

– Universal access to life saving vaccines = equity – Who is excluded from national programmes?

› Poor, marginalized communities › Minority communities › Refugee and internally displaced children

• 1. Equity

– Universal access to life saving vaccines = equity – Who is excluded from national programmes?

› Poor, marginalized communities › Minority communities › Refugee and internally displaced children

Highest risk Highest mortality Greatest need

Average mortality 5/10,000/day

• 1. Equity
• 2. Learn from our mistakes
• 3. Lifesaving vaccines out of the private sector
• 4. Eliminate billion dollar vaccines
• 5. Clarify role of industry
• 6. Leadership role for major agency