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10
Vaccine Safety Issues at the Turn of the 21 st Century Laura Conklin, MD Global Vaccine Safety Summit December 3, 2019

Transcript of µ Z d µ v v µ Ç - WHO...WKd^ A } µ o } Z } ] Z Ç ] Ç v } u V ZW^ A } u o Æ P ] } v o ] v Ç...

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Vaccine Safety Issues at the Turn of the 21st

CenturyLaura Conklin, MDGlobal Vaccine Safety SummitDecember 3, 2019

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21st Century Context

• Sustaining the gains in global vaccination programs requires maintaining public trust in both vaccine efficacy and vaccine safety

• Key vaccine safety issues reviewed by GACVS 1998-2019:

• Use of thiomersal in multi-dose non-live vaccines• Aluminium adjuvants used with several non-live

vaccines• Autism and autoimmunity as a possible

consequence of vaccination• A risk of immune overload with increasing

numbers of vaccinations• Nonspecific detrimental effects of vaccination Source: WHO/UNICEF coverage estimates 2018 revision, July 2019.

Immunization Vaccines and Biologicals, (IVB), World Health Organization

Global and Regional Immunization Coverage of DTP3-containing Vaccines, 1980-2018

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Aluminum adjuvants

• Enhances natural immune response• Early 20th century, aluminum has been used as an

adjuvant to immunization in a variety of forms• Public concerns focused on potential

developmental delay and auto-immune conditions • Data reviewed 1999-2012

• Epidemiological studies: Often seriously flawed methodology

• Clinical trials and FDA models: body burden below US regulatory thresholds

• GACVS conclusions• Evidence on the safety of aluminum adjuvants is

overwhelmingly reassuring• Continued research on pharmacokinetics of aluminum in

vaccines could further validate and improve upon the current models

MMF = Macrophagic myofasciitis

GACVS report

Exposure Outcome Link

1999 Sept Aluminum MMF Link

2002 June Aluminum MMF Link

2003 Dec Aluminum MMF Link

2004 June Adjuvants (general)

General safety Link

2004 Dec Adjuvants (general)

General safety Link

2005 Dec Adjuvants (general)

General safety Link

2012 June Aluminum Autism Link

Aluminum Pharmaco-kinetics

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Thiomersal

• Vaccine preservative metabolized into ethylmercury

• Public concerns re: neurotoxic effects based on methylmercury

• Removed from immunization schedule in the US as a precaution

• Data reviewed 2002-2012• Pharmacokinetic studies• Large epidemiological studies

• GACVS conclusions• Cumulative exposure from childhood

vaccinations does not result in toxic levels of ethylmercury

• Thiomersal-containing vaccines do not increase the risk of autism or other neurodevelopmental outcomes

• No additional studies warranted

GACVS report

Exposure Outcome Link

2002 June DTP Neurodev delay Link

HepB Leukemia

2003 June HepB, other General safety Link

2004 Dec Thiomersal (animal models)

Autism, Neurodev delay

Link

2005 June Thiomersal Mercury levels Link

2008 June HepB Mercury levels Link

Thiomersal Neuropsych. performance

2012 June Thiomersal Mercury levels, autism,Neurodev delay, special risk groups

Link

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Autism • Current evidence supports predominantly genetic

disorder with an inheritance of up to 80%• Public concerns focused on autism link to multiple

sources• Data reviewed 2002-2012

• Large, well-controlled epidemiological studies in multiple countries

• Over 2.5 million children

• GACVS conclusions• Abundance of high quality data• Vaccines do not increase the risk of autism

• Additional data• Taylor et al: Vaccines are not associated with autism: an

evidence-based meta-analysis of case-control and cohort studies, Vaccine 2014

• Hviid at al: Measles, Mumps, Rubella Vaccination and Autism: A Nationwide Cohort Study, Ann Intern Med 2019

GACVS report

Exposure Outcome Link

2002 June DTP Neurodev. delay Link

2002 Dec Multiple Autism Link

2004 Dec Multiple Autism, Neurodev. delay

Link

2012 June Aluminum Autism Link

2012 June Thiomersal Mercury levels, autism, Neurodev. delay, special risk groups

Link

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Autoimmune conditions• Wide variety of different pathologies • Largely based on the concept of molecular

mimicry • Data reviewed 2002-2016

• Controlled trials, observational studies, and epidemiological analyses

• Multiple countries and sub-populations• Multiple outcomes • Multiple vaccines

• GACVS conclusions• Small elevated risk of GBS after influenza vaccination

but lower than natural infection• Temporal association not sufficient to support causal

relationship• Global evidence supports the fact that vaccines do

not increase the risk of auto-immune diseases• Communication on safety of HPV released in 2019

MS = Multiple Sclerosis; GBS = Guillain=Barre Syndrome; POTS = postural orthostatic tachycardia syndrome; CRPS = complex regional pain syndrome

GACVS report

Exposure Outcome Link

2002 June HepB MS LinkInfluenza Bell’s Palsy

2003 Dec Influenza GBS, MS, optic neuritis Link

2005 Dec HepB Chronic Fatigue LinkMeningococcal GBS

2006 Nov Meningococcal GBS Link2007 June Meningococcal GBS Link2007 Dec Influenza, DTP

Tetanus, Mening.GBS Link

HepB Rheumatic arthritisMeningococcal Chronic FatigueRotavirus Kawasaki’s

2008 Dec HPV Central demyelinating disease, other

Link

2013 June HPV GBS, allergic reaction Link2013 Dec HPV MS, other Link2015 Dec HPV GBS, POTS, CRPS, other Link

Influenza (H1N1) narcolepsy2016 Dec Influenza (H1N1) narcolepsy Link

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Immune overload• Number of antigens delivered during infancy and

childhood increased• “Overload” poorly defined• Resulting in practice of delayed or alternative dosing

schedules• Data reviewed in 2006

• Vaccines delivered concomitantly or multi-component• Multiple exposures, multiple outcomes • Different populations (malnutrition, natural exposures)

• GACVS conclusions• Strong evidence on the ability of the immune system to

handle multiple vaccinations• Available evidence did not support the hypothesis that

vaccines weaken or harm the immune system

• Additional data• Hough-Telford et al., Vaccine Delays, Refusals, and Patient

Dismissals: A Survey of Pediatricians. Pediatrics, 2016

GACVS report

Exposure Outcome Link

2006 June Multiple (MMR, DTaP, Hib, other)

antibody concentrations, disease outcomes

Link

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Non-specific effects (NSE)• Theorized protection or susceptibility to non-targeted infections • Data reviewed 2002-2008

• Observational studies• Meta-analyses• Methodological papers

• GACVS conclusions• Caution is warranted regarding bias• Evidence on NSE are not sufficient to warrant changes in global policy• Claims of DTP increasing childhood mortality are not based on known

biological mechanisms and have not been shown to be scientifically reproducible

• Further studies specifically designed to address both positive and negative NSE needed

• Additional data• SAGE NSE working group 2014• Higgins, J.P., et al., Association of BCG, DTP, and measles containing

vaccines with childhood mortality: systematic review. BMJ, 2016• Sorup, S., et al., Simultaneous vaccination with MMR and DTaP-IPV-Hib

and rate of hospital admissions with any infections: A nationwide register based cohort study. Vaccine, 2016

GACVS report

Exposure Outcome Link

2002 June DTP NSE, child mortality

Link

2003 Dec DTP, BCG NSE, child mortality

Link

2004 June DTP NSE, child mortality

Link

2008 June DTP NSE, child mortality

Link

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Conclusions and Future Implications• Over 20 years, GACVS has reviewed scientific studies from

multiple disciplines and populations to inform conclusions on key safety issues

• Continued safety monitoring is critical to address public concerns and maintain trust

• New vaccines, new adjuvants, new populations• Only 64% of countries met WHO minimum criteria for a

functional safety surveillance system in 2015

• Role of GACVS will continue to be important in summarizing the evidence for global immunization programs

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Thank youPosition paper contributors:Laura Conklin (US CDC)Anders Hviid (SSI DK)Walt Orenstein (Emory University)Andrew Pollard (University of Oxford)Melinda Wharton (US CDC) Patrick Zuber (WHO)


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