1 10 october 2015 tony moody md duke pediatric infectious diseases vaccines: successes, failures,...
TRANSCRIPT
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10 October 2015Tony Moody MD
Duke Pediatric Infectious Diseases
Vaccines:Successes,
Failures,Resistance,
and UnexpectedBenefits
Image obtained from the Library of Congres, WPA Poster Project.
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or How I Learned to Stop Worrying and Love the Shot
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Disclosures
Advisory board for GSKBelimumab Pregnancy Registry
Chief Medical Officer of theDuke Human Vaccine Institute
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Vaccine-Preventable Deaths
2001 WHO Estimates
global actual / global prevented
diphtheria 5,000 / 73,000
pertussis 301,000 / 1 million
measles 676,000 / 1.2 million
Hib 463,000 / 5,000
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What have we done wrong?
1. Child mortality very low in US
2. Lack of understanding?
3. Failure to appreciate risk
4. Correlation = causation?
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Boston 1721
Image obtained from the MIT OpenCourseware site
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Cotton Mather (1663-1728)
Boston 1721 smallpox epidemic
Onesimus (slave) variolation
Image courtesy ofthe Clendening History of Medicine Library,
University of Kansas Medical Center
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Definitions
variolation ninoculation with smallpox material
derived from the Latinvariola (pox / pustule)
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Cotton Mather (1663-1728)
Boston 1721 smallpox epidemic
Onesimus (slave) variolation
Dr. Zabdiel Boylston son + two slaves
death rate 1:12 → 1:40
Image courtesy ofthe Clendening History of Medicine Library,
University of Kansas Medical Center
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Image obtained viathe Lampeter Corpus of
Early Modern English Tractsat Chemnitzin University, Germany
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Edward Jenner (1749-1823)
investigated claims of immunity after cowpox
Image courtesy ofthe Clendening History of Medicine Library,
University of Kansas Medical Center
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12Image courtesy of the Clendening History of Medicine Library, University of Kansas Medical Center
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Definitions
vaccination nthe act of administering material to induce or increase specific immunity
derived from the Latinvacca (cow)
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Edward Jenner (1749-1823)
investigated claims of immunity after cowpox
1796: vaccinated James Phipps (8yo)
subsequently challenged with smallpox
Image courtesy ofthe Clendening History of Medicine Library,
University of Kansas Medical Center
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15Image obtained from the National Library of Medicine
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Louis Pasteur (1822-1895)
developed principle of attenuation
developed attenuated rabies vaccine
post-exposure vaccination of Joseph Meister (1885)
Image courtesy ofthe Clendening History of Medicine Library,
University of Kansas Medical Center
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Emile Roux (1853-1933)
physician working with L Pasteur
refused to inoculate J Meister
Image courtesy ofthe Clendening History of Medicine Library,
University of Kansas Medical Center
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Three eras of vaccine development
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First era
Anti-bacterial vaccines
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20Image obtained from the National Library of Medicine, History of Medicine Collection
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Paul Ehrlich (1854-1915)
Dale H. Paul Ehrlich, born March 14, 1854Br Med J 1(4863): 659–663 (1954).
Emil von Behring (1854-1917)
MacNalty A. Emil von Behring, born March 15, 1854Br Med J 1(4863): 668–670 (1954).
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22Image obtained from the National Library of Medicine, History of Medicine Collection
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B pertussis—epidemiology
Until the mid 1940s, accounted for more deaths in children less than one year old than measles, scarlet fever, diphtheria, poliomyelitis and meningitis combined
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Camille Guérin (1872-1961)
Image obtained viaen.wikipedia.org
Albert Calmette (1863-1933)
Image courtesy ofthe Clendening History of Medicine Library,
University of Kansas Medical Center
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Timeline of Vaccines
1879: cholera
1885: rabies
1890: tetanus
1896: typhoidfever
1897: bubonicplague
1921: diphtheria
1925: tuberculosis
1926: scarlet fever
1927: pertussis
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Second era
Cell culture leading toanti-virus vaccines
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Image from Nobel.orgvia Wikipedia
John Enders(1897-1985)
developed tissue culturetechniques to grow viruses
1954 Nobel Prize withThomas Weller andFrederick Robbins
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Image obtained fromthe CDC Public Health Image Library
Image via WikipediaOriginally from Deutsches Grünes Kreuz
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30Nathanson & Langmuir, Am J Hyg 78: 29-60 (1963).
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Polio vaccine
The Cutter Incident
>380,000 doses of Cutter vaccine
>300,000 school clinics
~120,000 from “high rate lots”
initial paralysis in inoculated limb
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Polio vaccine
The Cutter Incident
vaccine given between13 – 27 April 1955
est. 40,000 infections
51 paralyzed / 5 deaths
89 family contacts paralyzed
5 family contacts died
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33Nathanson & Langmuir, Am J Hyg 78: 29-60 (1963).
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34Image obtained from the CDC Public Health Image Library
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RSV vaccine
Formalin-Inactivated RSV Vaccine
1966-1967 trial
children 2 mos to 9 yrs
good rise in Ab titers
during subsequent season
80% of vaccinees hospitalized (2)
5% of controls (0)
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RSV vaccine
Formalin-Inactivated RSV Vaccine
skewing of T cell responses
overactive pulmonary immune responses
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Timeline of Vaccines
1932: yellow fever
1937: typhus
1945: influenza
1952: polio (Salk)
1954: Japaneseencephalitis
1954: anthrax
1962: polio (Sabin)
1963: measles
1967: mumps
1970: rubella
1974: chicken pox
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Third era
Molecular biology
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Timeline of Vaccines
1977: Streptococcus pneumoniae
1978: Neisseria meningitidis
1981: hepatitis B
1985: Haemophilus influenzaetype b (HiB)
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Problems in the 1980/90s
Hepatitis B vaccine derived from sera of infected persons (HIV-1 risk).
Polysaccharide vaccines associated with poor response in infants.
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42Image obtained from the CDC Public Health Image Library
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Rotavirus vaccine
RotaShield®
licensed 1998
increased cases of intussusception
pulled from market in 1999
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44Murphy et al., N Engl J Med 344: 564-572 (2001).
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Rotavirus vaccine
Rotarix®: GSK rotavirus vaccine
has DNA from porcine circovirus 1
always had it, even in safety trials
voluntary suspension
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Rotavirus vaccine
Porcine circovirus 1
infects swine,causes no known disease
no known circoviruses infectinghumans
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Vaccine Contaminants
Vaccines are sometimes messy preparations.
Sometimes extra things get in the mix.
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Timeline of Vaccines
1992: hepatitis A
1998: Lyme dz
1998: rotavirus
2003: LAIV
2006: HPV
1990: Hib cnjgt
1990: rHBV
2000: PCV7
2001: Men cnjgt
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Fourth era?
Rational vaccine design?
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Adapted from Haynes et al. B-cell-lineage immunogen design in vaccine development with HIV-1 as a case study.Nat Biotechnol 30(5): 423–433 (2012). [PMC3512202]
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Correlates of Protection
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Correlates of Protection
It’s Antibody,except when it isn’t.
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56SA Plotkin, Immunologic correlates of protection induced by vaccination. PIDJ 20: 63-75 (2001).
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57SA Plotkin, Immunologic correlates of protection induced by vaccination. PIDJ 20: 63-75 (2001).
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Final Thoughts 1/3
Bad studies, misinformation, & the tyranny of small numbers
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Central-nervous-system demyelinationafter immunisation with recombinanthepatitis B vaccineHerroelen L, de Keyser J, Ebinger G.Lancet 338: 1174-1175 (1991).
cohortone pt w/ MSone pt w/o MS
characteristicsboth +ve for HLA DR2 & B7
resultssix weeks after booster doses → demyelination
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Association between type 1 diabetesand Haemophilus influenzae type bvaccination: birth cohort studyKarvonen M, Cepaitis Z, Tuomilehto J. BMJ 318: 1169-1172 (1999).
cohortFinland 128,936 unvaccinated 116,352 vaccinated
characteristicspatient groups are from pre- and post-vaccine eras
resultsoverall rates of DM 1 upno correlation w/ vaccines
subsequent letters ?’d the statistical methods and the data presentation
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thimerosal / thiomersal
S
Na+
O-O
Hg
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JAMA 110(5) 337-343 (1938)
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Thimerosal and the Occurrence ofAutism: Negative Ecological EvidenceFrom Danish Population-Based DataMadsen KM, Lauritsen MB, Pedersen CB, Thorsen P, Plesner A-M,Andersen PH, Mortensen PB. Pediatrics 112: 604-606 (2003).
cohortconvergence of multiple Danish public healthcare databases
characteristicsincidence of autism
resultsrates of autism went up after thimerosal was removed from vaccines
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Ileal-lymphoid-nodular hyperplasia,non-specific colitis, and pervasivedevelopmental disorder in childrenWakefield AJ, Murch SH, Anthony A, Linnell J, Casson DM, Malik M,Berelowitz M, Dhillon AP, Thomson MA, Harvey P, Valentine A, Davies SE,Walker-Smith JA. Lancet 351: 637-641 (1998).
cohort12 children w/ PDD14 matched controls
characteristics8 after measles vaccine1 after measles infection2 others immunized
resultsnodular hyperplasia seen in PDD pts / not in ctls
methylmalonic acid excretion elevated
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Wakefield Retraction
February 2004
10 / 13 original authors retract
Wakefield working forLegal Aid Board
Wakefield named in patent forpotential MMR competitor
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68Deer, BMJ 340: 838-841 (2010).
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Wakefield Retraction
April 2010 article
original paper
11/12 children with chronic“non-specific colitis”
original path reports
8/11 pathology reports normal
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Final Thoughts 2/3
Can vaccines have off-target benefits?
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URTI/LRTI Sepsis
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ResultBCG given to LBW infants
reduced all-cause mortality.
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Final Thoughts 3/3
Are we the victims of our own success?
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What have we done wrong?
1. Child mortality very low in US
2. Lack of understanding?
3. Failure to appreciate risk
4. Correlation = causation?
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76Hoyert DL. 75 years of mortality in the United States, 1935-2010. NCHS Data Brief (88): 1–8 (2012).
Life Expectancy
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77Fine P, Eames K, Heymann DL. “Herd Immunity”: A Rough Guide. Clin Infect Dis 52(7): 911–916 (2011).
Herd Immunity
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78Fine P, Eames K, Heymann DL. “Herd Immunity”: A Rough Guide. Clin Infect Dis 52(7): 911–916 (2011).
Herd Immunity
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1. “I’m protected because others are vaccinated.”
2. “I won’t be exposed. /I am not going to travel to an endemic area.”
3. “So what if I get sick.”
Herd Immunity
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1. The world has shrunk.
2. Adult disease often associated with worse outcomes.
3. More immunocompromised persons.
4. “Nostalgia”—misremembered childhood disease.
Risks of Infection
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1. MMR and autism
2. Thimerosal and autism
3. HBV and multiple sclerosis
4. Hib and diabetes
Correlation ≠ Causation
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82Image from Wikipedia.
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83Sies, Nature 332: 495 (1988).
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84Sies, Nature 332: 495 (1988).
storksbabies