U. S. Immunizations

Morbidity from Vaccine-Preventable Diseases

Maximum and Current Reported Morbidity from Vaccine-Preventable Diseases Events, United States

Effects Of Vaccination On Disease Incidence

Notable Vaccine Adverse IncidentsDue to Production Errors

• Pasteur rabies vaccine (1880s)

• Seizure, paralysis, coma in 1/230 immunized

• 1942 US military yellow fever vaccine

• Formulated with human serum

• Contaminated with infectious hepatitis B virus

• 330,000+ infected; 50,000+ with disease; 62 deaths

• 1955 Cutter Laboratories incident

• One of five companies first contracted to produce Salk vaccine

• Failed to inactivate vaccine preparation (insufficient formalin duration)

• 120,000 infected; 40,000 mild polio; 200 paralyzed; 10 deaths

• Acute encephalopathy after whole-cell pertussis vaccine

• Acute arthropathy following rubella vaccine

• Thrombocytopenia following measles virus-containing vaccine

• Guillain–Barré syndrome (GBS) after swine flu vaccine

• Paralytic polio following live, attenuated oral polio vaccine (OPV)

• Anaphylaxis following receipt of vaccines containing egg proteins or gelatin

Notable Vaccine Adverse IncidentsDue to Rare Biological Events

Methods of Monitoring Immunization Safety

• Because vaccines are given to healthy children and adults, a higher standard of safety is generally expected of immunizations compared with other medical interventions

• Tolerance of adverse reactions to pharmaceutical products given to healthy people, especially healthy infants and toddlers, to prevent certain conditions is substantially lower than to products to treat people who are sick

• This lower tolerance for risks from vaccines translates into a need to investigate the possible causes of much rarer adverse events after vaccinations than would be acceptable for other pharmaceutical products

Prelicensure Evaluations Of Vaccine Safety

• Phase I trials usually include fewer than 20 participants and can detect only extremely common adverse events

• Phase II trials generally enroll 50 to several hundred people.

• When carefully coordinated, important insight into the relationship between concentration of antigen, number of vaccine components, formulation, effect of successive doses, and profile of common reactions can be drawn

• Sample sizes for Phase III vaccine trials are based principally on efficacy considerations, with safety inferences drawn to the extent possible based on the sample size (approximately 102 to 105) and the duration of observation (often <30 days)

The Brighton Collaboration

• http://www.brightoncollaboration.org

• Enhancing pre-licensure safety assessment of vaccines

• Established to develop and implement globally accepted standard case definitions for assessing adverse events following immunizations in both pre- and post-licensure settings

• Without such standards, it was difficult if not impossible to compare and collate safety data across trials in a valid manner

• In the large multi-site Phase III infant DTaP trials, definitions of high fever across trials varied by temperature (39.5°C vs. 40.5°C), measurement (oral vs. rectal), and time (measured at 48 vs. 72 hours)

Post-Licensure Evaluations Of Vaccine Safety

• Because rare reactions, reactions with delayed onset, or reactions in subpopulations may not be detected before vaccines are licensed, post-licensure evaluation of vaccine safety is critical

• Historically, this evaluation has relied on passive surveillance and ad hoc epidemiologic studies, but, more recently, Phase IV trials and pre-established large linked databases (LLDBs) have improved the methodologic capabilities to study rare risks of specific immunizations

• Such systems may detect variation in rates of adverse events by manufacturer or specific lot

National Childhood Vaccine Injury Act

• NCVIA established by Congress in 1986

• Mandated reporting of adverse events

• The Vaccine Adverse Events Reporting System (VAERS)

• Implemented jointly by the CDC and the FDA in 1990

• Provide a unified national focus for collection of all reports of clinically significant adverse events

• After reporting, cases evaluated individually to assess if event was genuinely associated with vaccination or coincident

• If a vaccine was found to be responsible, the Federal Government compensates parents

• Protects industry from litigation because without it companies will stop producing vaccines

The VAERS Form

Vaccine Safety

Autism Spectrum Disorders (ASD)

• A family of pervasive developmental disorders (PDD) that range from mild to severe in phenotype

• Typically is first noticed by parents when children are 2 or 3 years of age

• This is also when routine vaccinations are administered

• Incidence

• Prior to 1990 in the United States, the incidence of autisms was 1 in several hundred

• Currently, the incidence is about 1 in 60 children

Vaccine Safety

• FUD: Fear, uncertainty, doubt

• The antivaccine movement is based upon FUD

• Supposed connection between vaccines and autisms

• In 1991, two new vaccines containing thimerosal, an organic mercury-based preservative, were added to the childhood immunization list

• In 1992, the incidence of ASD began to rise

• This correlation led to some assuming a causal relationship between vaccines and ASD

• The result of this movement has been

• Increased incidence of vaccine-preventable disease

• Deaths of children

A Genetic Basis To ASD

• A clear genetic linkage is associated with some, and perhaps all, ASDs

• Autisms occur in 3.5 boys for every girl

• At least 16 loci have been implicated, including X chromosome loci

• Strongly implies a multigenic trait

• There may be environmental factors involved

• The biological bases of ASDs are largely unknown

• No animal model (complex behavioral disorder)

Engrailed Homeobox 2One Example: EN2 (alias - AUTS1)

Functions of EN2

• A transcription factor

• It can be transported between cells in culture by unconventional secretion and internalization mechanisms

• EN-2 had been considered to be an important transcriptional factor during embryonic development

• It controls synaptic formation and axon projections

• Some relationships between EN-2 and Parkinson's disease.

• Two polymorphisms in this gene occur in some Chinese children with ASD

The Wakefield Paper

• Wakefield et al. Ileal-lymphoid-nodular hyperplasia, non-specific colitis and pervasive developmental disorder. Lancet. 1998. 351:637-41.

• Paper asserted that attenuated measles virus in MMR vaccine was associated with autism• Half of the 12 children in the study had exhibited symptoms of autism

prior to vaccination

• Wakefield was a paid consultant for Legal Aid Board, a British legal fund representing parents of children suing the vaccine’s maker over alleged injuries

• Wakefield was working on a measles vaccine himself

• Paper was retracted in 2004 by 10 of the 13 authors (one could not be located, and Wakefield and another refused the retraction)

• Journal (The Lancet) officially retracted the paper in 2010

• This paper and Wakefield’s subsequent public campaign dramatically affected vaccination rates in Great Britain• As of 2008, measles is endemic in Great Britain again

The FUD of Thimerosal

• All claims of thimerosal’s in vivo toxicity are based upon other forms of mercury

• Mercury salts (e.g., mercury chloride) that cross membranes by diffusion

• Elemental mercury

• Methylmercury that cross membranes by diffusion

• Inferences are inaccurate because the symptomology of these compounds are completely different than what is observed in autistic children

Thimerosal As A Vaccine Preservative

• Bacteriostatic agent used in inactivated vaccines

• An organic mercury

• Principal metabolic product is ethylmercury

• Cannot cross plasma membranes by diffusion (requires active transport)

• Ethylmercury interacts with thiol groups found on bacterial cell walls and other proteins (including viruses and fungi)

• Used in vaccines and other medical injectables since the 1930s

• Inexpensive and highly effective

• Low toxicity

• >90% is excreted within 30 days

Thimerosal and the Danish Study• Denmark has extensive medical records of its citizens

• Abandoned thimerosal in childhood vaccines in 1992

• Evaluated the incidence of autisms in children immunized with thimerosal-free and thimerosal-containing vaccines

• Results• 956 autistic children

• 3.5:1 male:female ratio

• From 1970 to 1990, no increased incidence of autisms was observed

• After removal of thimerosal, the incidence of autisms began to increase

Madsen et al. Thimerosal and the occurrence of autism: negative ecological evidence from Danish population-based data.

Pediatrics. 2003. 12:604-6.

Thimerosal removed

The Institute of Medicine’s Report

• IOM is the National Academy of Science’s public health review board

• They reviewed the data and concluded that

• No evidence exists supporting a link between thimerosal and autisms

• However, it is plausible that thimerosal may have an impact on some children

• Recommended removal of thimerosal from childhood vaccines

• FDA approved and thimerosal was removed from childhood vaccine formulations in 2001

• This removal has had no impact on the incidence of autisms in the United States

Incidence of ASD in the United States

Thimerosal removed

Why Has ASD Incidence Increased?

• Change in definition

• Autism in 1980s was a narrowly-defined term

• Autistic persons were largely incompetent

• In about 1990 it was broadened to include mild and moderate PDD

• In 1988, the Congress increased funding for special education

• Is it all that surprising that the incidence of autism (now including other “forms” of autism) has increased?

Gardasil Vaccine Safety

Slade et al. 2009. JAMA. 302:750

Gardasil Vaccine• Prevention of cervical cancers caused by human

papillomaviruses

• Recombinant vaccine

• Four serotypes in formulation (quadrivalent)

• 6 (genital warts)

• 11 (genital warts)

• 16 (cancer)

• 18 (cancer)

• Approved by the FDA on 8 June 2006

• Advisory Committee on Immunization Practices guidelines

• Routine for females

• Three doses i.m.

• 0, 2 and 6 month schedule

70% of all cervical cancers

90% of all cervical warts

• Virus-Like Particle vaccine (HPV VLP vaccine)

• Recombinant major capsid (L1) protein of HPV Types 6, 11, 16, and 18

• The L1 proteins are produced by separate fermentations in recombinant Saccharomyces cerevisiae CANADE 3C-5 (Strain 1895)

• self-assembled into VLPs

• VLPs for each type are purified and adsorbed on aluminum-containing adjuvant sulfate

• Each 0.5 mL dose contains approximately

• 20 µg of HPV 6 L1 protein

• 40 µg of HPV 11 L1 protein

• 40 µg of HPV 16 L1 protein

• 20 µg of HPV 18 L1 protein

• 225 µg of aluminum (as amorphous aluminum hydroxyphosphate sulfate adjuvant)

• 9.56 mg of sodium chloride

• 0.78 mg of L-histidine

• 50 µg of polysorbate 80

• 35 µg of borax,

• water

• it does not contain a preservative or antibiotics

Gardasil Vaccine Formulation

Prelicensure Clinical Trials

• 21,000 women

• 90% to 100% effective in preventing:

• Precancerous cervical, vaginal and vulvar lesions

• Genital warts

• Adverse events following immunization (AEFI)

• 60% in placebo group

• 59% in vaccinated group

• Symptoms

• Headaches

• Fever

• Nausea

• Severe injection site reaction

Postlicensure Safety• As of 31 December 2008: >23,000,000 doses

administered• http://www.cdc.gov/vaccinesafety/vaers/gardasil.htm

• AEFI data from VAERS (2.5 years)• U.S. data only• Serious AEFI as defined by 21 CFR §314.80

• http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=314.80

• Case reviews and separate analyses for• syncope• dizziness• nausea• headache• local injection site reactions• hypersensitivity reactions including anaphylaxis• Guillain-Barre´ syndrome (GBS)• transverse myelitis• pancreatitis• venous thromboembolic events (VTEs)• deaths• pregnancy outcomes

Separating Signal From Noise

• Is an adverse event due to the vaccine or is it just coincidence?

• Gardasil and Guillain-Barre´ syndrome

• Incidence in vaccinated 9-26 year old females was 0.3 per 100,000 person years

• Incidence in unvaccinated 9-26 year old females is 1.57 per 100,000 person years

Severity of qHPV Adverse Events Following Immunization in the

United StatesAge Deaths

NonfatalSerious

Nonserious Total No.Reporting

Ratea

<9 0 0 41 41 0.2

9-10 0 11 160 171 0.7

11-12 2 60 950 1012 4.4

13-17 9 332 4009 4350 18.9

18-26 9 262 3687 3958 17.2

>26 0 16 258 274 9.9

Unknown 12 59 2547 2618

Total 32 740 11652 12424 53.9

a Reports per 100 000 doses distributed

Deaths Following Gardasil Administration• 32 deaths

• 8 could not be verified• 4 reported by manufacturer but not

verified• 20 verified deaths• 14 after qHPV alone• 6 after qHPV and other vaccinations

• By dose• 9 after dose 1• 5 after dose 2• 6 after dose 3

• No age clustering• Mean time of onset = 39 days• Range of 2-288 days

• 4 deaths were unexplained

Deaths Following Gardasil Administration

• Causes of the 20 verified deaths

• 4 unexplained

• 2 diabetic ketoacidosis (1 with pulmonary embolism)

• 1 from prescription drug abuse

• 1 of juvenile amyotropic lateral sclerosis

• 1 of Neisseria meningioencephalitis

• 1 influenza B viral sepsis

• 3 pulmonary embolism (1 with ketoacidosis, 2 taking oral contraceptives which increase incidence of emboli)

• 6 cardiac-related deaths (4 arrhythmias, 2 myocardiatis)

• 2 due to idiopathic seizure disorder