Syd Spiesel

1
Pros and Cons of Newer Vaccines

• Syd Spiesel
• May 14, 2009

2
disclaimer

• I am an honest person and I am beholden to no
  one at least, no commercial entity
• I have chosen to avoid using any trade names

3
intention

• to point out some important aspects of newer
  vaccines extrapolating from historical contexts
• changes in manufacturing methods
• ways that potency can be enhanced
• ways that safety can be improved
• ways that administration can be improved
• value of immunization
• economic considerations

4
Early history of vaccines

• really early history
• King Mithridates VI of Pontus (132-63 BCE)

5
More early history of immunization

• 6-10 Century CE crude immunization against
  smallpox begins in China
• clothes from infected patients
• insufflation of powdered aged smallpox scabs
• variolation skin inoculation from scab sources

6
A little more history

• variolation
• 13th C CE introduced into Egypt
• 1721 introduced into England (Lady Montague)
  and North America (Cotton Mather)
• 1776 smallpox disrupts Colonial army in Quebec
  Canada remains British
• 1777 Washington orders variolation for troops
• 1798 Jenner describes vaccination
• 1863 Gettysburg Address Lincoln prodromal for
  smallpox

7
The early science of vaccines

• Pasteur
• 1880 chicken cholera vaccine
• 1881 anthrax vaccine
• 1885 human rabies vaccine

8
Vaccines in the 20th Century

• diphtheria
• upper respiratory disease
• sore throat, low fever
• malaise
• US epidemiology
• mortality 10
• 1920s 15,000 deaths/yr
• now 5 cases/year

• pseudomembrane adherent to tonsils , pharynx,
  nasal lining
• bull neck

9
Vaccines in the 20th Century

• diphtheria
• Corynebacterium diphtheriae toxin
• blocks cellular protein synthesis
• kills mammalian cells leading to
• life-threatening swelling in throat
• cardiomyopathy
• peripheral nerve demyelination and sensory
  neuropathy
• skin damage

10
Vaccines in the 20th Century

• diphtheria vaccines
• 1909 TAT toxin-antitoxin (Theobald Smith)
• 1920 diphtheria toxoid (Ramon)
• 1926 alum-precipitated toxoid
• 1948 DPT diphtheria toxoid-pertussis
  vaccine-tetanus toxoid

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Vaccines relevant issues lessons

• diphtheria vaccines
• vaccines powerful in ability to ameliorate misery
• vaccines can cause harm (TAT serum sickness)
• antigenicity ? toxicity (toxoiding)
• potency can be enhanced by adjuvants (alum
  precipitation)
• antigens can be mixed without loss of potency or
  increased side-effects (DPT)
• precautions against vaccine contamination
  necessary (Bundaberg disaster)

12
Vaccines new vaccine issues

• 1. safety from contamination
• multiple dose containers must contain a
  preservative in case of the introduction of a
  contaminant
• 1928 Bundaberg disaster
• thimerosal
• phenoxyethyl alcohol
• single-dose vaccines manufactured under extremely
  strict asepsis can be (and usually are)
  preservative-free
• manufacturing and distribution are very expensive
• one intention reassurance to dispel public
  anxiety about immunization

13
Vaccines in the 20th Century

• tetanus (lockjaw)
• associated with injury especially dirty
  puncture wounds rusty nails as delivery systems
• prolonged contraction (intense spasm) of skeletal
  muscle -- especially jaws
• soldiers , infants, and elderly at greatest risk
• currently 1,000,000 cases/yr worldwide with
  30-50 mortality
• US 100 cases/yr with 5 mortality

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Vaccines in the 20th Century

• tetanus - opisthotonos

15
Vaccines in the 20th Century

• tetanus - neonatal

16
Vaccines in the 20th Century

• tetanus vaccines
• 1914 horse-derived immune serum used
  prophylactically and therapeutically in WW I
• 1927 toxoid also combination with diphtheria
  toxoid (Ramon)
• 1938 first commercial toxoid available in US
• 1941 US routine military prophylaxis WW II
• Japanese wounded -- 5 tetanus symptoms
  mortality 70
• US wounded 12 cases in 2,730,000 wounded
• 8/12 evaded immunization

17
Vaccines relevant issues lessons

• tetanus vaccine
• vaccines powerful in ability to ameliorate misery
• vaccines can cause harm (TAT serum sickness)
• antigenicity ? toxicity (toxoiding)
• potency can be enhanced by adjuvants (alum
  precipitation)
• antigens can be mixed without loss of potency or
  increased side-effects (DPT)

18
Vaccines relevant issues lessons

• tetanus vaccine
• vaccines powerful in ability to ameliorate misery
• vaccines can cause harm (TAT serum sickness)
• antigenicity ? toxicity (toxoiding)
• potency can be enhanced by adjuvants (alum
  precipitation)
• antigens can be mixed without loss of potency or
  increased side-effects (DPT)

19
Vaccines in the 20th Century

• pertussis (whooping cough)
• minimal fever (or none)
• gradually worsening cough x 1-2 weeks
• paroxysms of coughing interspersed with whoop
  as patient takes a breath
• small vessel hemorrhages in skin, eyes, brain
• profuse mucus discharge

20
Vaccines in the 20th Century

• pertussis (whooping cough)
• cause -- small bacterium Bordetella pertussis
• non-invasive
• several locally-active toxins
• antibiotics useless for treatment valuable for
  public health

21
Vaccines in the 20th Century

• pertussis (whooping cough)

22
Vaccines in the 20th Century

• pertussis (whooping cough)
• 1914 whole-cell vaccine
• 1948 standardization of manufacture and
  testing integration into DTP
• Standard method bacteria grown on solid culture
  medium, harvested by raking, bacteria killed with
  thimerosal, toxin (partly) heat-inactivated
• 1965 experimental acellular vaccine
• 1980s commercial liquid culture of B.
  pertussis
• 1981 Japanese acellular vaccine
• 1991 US acellular vaccine licensed

23
Vaccines relevant issues lessons

• pertussis vaccine
• vaccines powerful in ability to ameliorate misery
• antigenicity ? toxicity (purifying protective
  antigen led to dramatic decrease in side-effects)
• potency can be enhanced by adjuvants (protective
  antigen of pertussis is, itself, a potent
  adjuvant)
• antigens can be mixed without loss of potency or
  increased side-effects (adjuvant effect of
  pertussis enhances the response to antigens given
  concomitantly)

24
Vaccines new vaccine issues

• 3. adjuvants to enhance the immune response to
  vaccines
• adsorption of antigens to particles of poorly
  soluble aluminum salts (alum-precipitated)
• delayed release of antigens from depot
• enhanced takeup by antigen presenting cells
• ?role of promoting local inflammation
• protective antigen of pertussis vaccine
• monophosphoryl lipid A (MPL -- low-toxicity
  derivative of LPS) a new adjuvant awaiting FDA
  approval for use in a new human papillomavirus
  vaccine
• stimulation of antigen presenting cells
• new adjuvants badly needed

25
Vaccines in the 20th Century

• poliomyelitis (3 serotypes)
• GI virus
• uncommon spinal cord motor neuron damage, leading
  to flaccid paralysis (lt1)
• still more rare brain stem disease, leading to
  paralysis of respiratory muscles
• epidemiology
• fecal-oral transmission
• prior to era of immunization, more common where
  hygiene good victims mainly middle-class
• higher risk of motor neuron involvement with
  increasing age

26
Vaccines in the 20th Century

• poliomyelitis

27
Vaccines in the 20th Century

• poliomyelitis

28
Vaccines in the 20th Century

• poliomyelitis vaccines
• 1955 Salk (inactivated) polio vaccine IPV
• 1961 Sabin (live oral) polio vaccine OPV
• epidemiological benefit incidental secondary
  transmission of vaccine strain
• epidemiological disbenefit incidental secondary
  transmission of vaccine strain after random
  mutation reversion to (neurotropic) wild type
• 1987 enhanced-potency IPV

29
Vaccines relevant issues lessons

• polio vaccine
• vaccines powerful in ability to ameliorate misery
• vaccines can cause harm
• Sometimes a bug and a feature are the same live
  polio vaccine virus can spread and so a single
  dose can accidently immunize many people but
  live polio vaccine can revert and regain
  neurotropism
• cultural values and politics may intrude on
  public health
• Polio almost eliminated in India until
  politically-fomented suspicion led to abandonment
  of immunization programs now polio re-emerging
  worldwide as a public health problem, with India
  a major source of epidemic disease

30
Vaccines in the 20th Century

• measles
• highly infectious
• historically, deadly especially to naïve
  populations
• even now 400,000 children die annually worldwide
• leading cause of blindness in African children
• fever, cough, conjunctivitis, and rash
• complications ear infections, pneumonia,
  meningitis, encephalitis

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Vaccines in the 20th Century

• measles

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Vaccines in the 20th Century

• measles vaccine
• 1963 killed virus vaccine (withdrawn 1967)
• poor immunity
• recipients at high risk for (very serious)
  atypical measles infection
• 1963 live attenuated vaccine (chick embryo
  fibroblast tissue culture)
• 1968 live further attenuated (also chick embryo
  fibroblast tissue culture)
• 1979 incorporated with mumps and rubella into
  MMR

33
Vaccines in the 20th Century

• mumps
• salivary gland (usually parotid) swelling and
  tenderness
• sometimes pancreatic or testicular inflammation
• meningoencephalitis
• formerly leading cause of deafness

34
Vaccines in the 20th Century

• mumps

35
Vaccines in the 20th Century

• mumps vaccine
• 1966 live virus (chick embryo fibroblast tissue
  culture)
• 1979 incorporated into measles-mumps-rubella
  combination vaccine

36
Vaccines in the 20th Century

• rubella (German measles)
• mild viral illness with rash, sometimes joint
  pain and swollen lymph nodes
• maternal infection during pregnancy (esp 1st
  trimester) very high risk of congenital
  abnormalities in fetus
• mental handicap, cataract, deafness, cardiac
  abnormalities

37
Vaccines in the 20th Century

• rubella (German measles)

38
Vaccines in the 20th Century

• rubella vaccine
• 1969 live virus (dog kidney tissue culture)
• 1979 live virus (human fibroblast culture)
• 1979 incorporated into measles-mumps-rubella
  combination vaccine

39
Vaccines relevant issues lessons

• rubella vaccine
• important public health issues (and precedent)
• this vaccine is of great public health value but
  is usually not beneficial to the recipients,
  themselves
• of no direct value for boys and men (the disease
  is insignificant for infants, children, and
  adults)
• Somewhat valuable for girls and women (since an
  immunized mother protects the fetus and it is
  the fetus at risk from rubella)
• The main value for everyone is a high level of
  herd immunity, which minimizes the risk of
  exposure of pregnant women, some of whom may be
  inadequately protected themselves

40
Vaccines in the 20th Century

• varicella
• very contagious viral illness
• very itchy skin rash
• small vesicles (blisters) which break and scab
  over
• sometimes severe complications
• pneumonia
• secondary bacterial infections
• early in pregnancy CNS, eye, spinal cord damage
• very late in pregnancy severe pneumonia and
  other complications
• shingles reactivation of virus from earlier
  chickenpox

41
Vaccines in the 20th Century

• varicella

42
Vaccines in the 20th Century

• varicella vaccine
• 1987 Oka strain vaccine licensed in Japan
• 1995 US licensed live virus (human fibroblast
  culture)
• 2005 incorporated into measles-mumps-rubella-var
  icella (MMRV) combination vaccine

43
Vaccines relevant issues lessons

• varicella vaccine
• economic trade-offs should we follow
  cold-blooded economic analysis in deciding
  whether to use a vaccine?
• expensive vaccine
• chicken pox only rarely (but sometimes!) causes
  serious illness or death
• but immunosuppressed contacts may be at high risk
• many parental work days lost to disease
• universal immunization almost eliminates small
  tickling exposures which boost immunity and
  (probably) decrease the prevalence of shingles
• at least 1 booster dose needed for kids
• very expensive zoster vaccine now needed for
  elderly

44
Vaccines new vaccine issues

• varicella vaccine
• higher reaction rate to MMRV than to MMR
  varicella
• febrile seizures

45
Vaccines in the 20th Century

• HIB (Hemophilus influenzae type B)
• bacterial infection
• invasive disease
• meningitis
• bacteremia
• epiglottitis
• septic arthritis

46
Vaccines in the 20th Century

• HIB (Hemophilus influenzae type B) meningitis

47
Vaccines in the 20th Century

• HIB (Hemophilus influenzae type B) epiglottitis

48
Vaccines in the 20th Century

• HIB (Hemophilus influenzae type B) vaccine
• 1965 PRP (capsular polysaccharide)
• B-cell vaccine only ineffective below 2 years
• 1987 PRP-D (diphtheria toxoid conjugate)
• poorly immunogenic for young children
• 1988 HbOC (HIB oligosaccharide linked to CRM197
  -- atoxic variant diphtheria toxin)
• 1989 PRP-OMP (meningococcal protein conjugate)
• strong response in young infants
• 1993 PRP-T (tetanus toxoid conjugate)
• 1993 combination with DTaP licensed

49
Vaccines in the 20th Century

• Streptococcus pneumoniae (pneumococcus)
• invasive disease (90 serotypes)
• bacteremia
• meningitis
• pneumonia
• otitis media

50
Vaccines in the 20th Century

• Streptococcus pneumoniae (pneumococcus)
• pneumonia

51
Vaccines in the 20th Century

• Streptococcus pneumoniae vaccines
• 1977 14-valent polysaccharide vaccine licensed
• 1983 23-valent polysaccharide vaccine licensed
• both are B-cell vaccines
• protection limited to 3-5 years
• ineffective below 2 years of age
• 2000 7-valent polysaccharide-CRM197 (atoxic
  diphtheria toxin) conjugate
• T-cell vaccine
• long-lasting protection
• effective in infants

52
Vaccines new vaccine issues

• pneumococcal conjugate vaccine
• 7-valent vaccine good, but not good enough
  additional strains needed for better coverage
• 10-valent vaccine in clinical trials
• 13-valent vaccine in clinical trials and on FDA
  fast-track to licensure
• economic issues another very expensive vaccine

53
Vaccines in the 20th Century

• Neisseria meningitidis (meningococcus)
• highly infectious
• often fulminant course
• septicemia
• shock
• meningitis
• hearing loss and neurological disabilities
• disseminated intravascular coagulation
• purpura
• gangrene and loss of digits and limbs
• myocarditis

54
Vaccines in the 20th Century

• Neisseria meningitidis (meningococcus)

55
Vaccines in the 20th Century

• Neisseria meningitidis (meningococcus)

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Vaccines in the 20th Century

• meningococcal capsular polysaccharide vaccine
• main US Europe serotypes C, Y, B, W-135
• main Sub-Saharan Africa serotype A
• 1978 US 4-valent (A, C, Y, W-135) capsular
  polysaccaride vaccine licensed
• B-cell vaccine ineffective after about 3 years
• 1999 England type C CRM197 conjugated vaccine
  introduced for routine use
• 2000 US 4-valent (A, C, Y, W-135) CRM197
  conjugated vaccine licensed
• T-cell vaccine very long (perhaps permanent)
  protection
• N. meningitidis B serotype inadequately
  antigenic for vaccine use, even if conjugated

57
Vaccines new vaccine issues

• meningococcal conjugate vaccine
• since the conjugate vaccine is effective at
  younger ages and since the vaccine appears to
  provide very long-lived immunity, expect this
  vaccine (now usually given around 6th grade) to
  be shifted to younger children. The vaccine is
  now licensed for 2 years and up and the illness
  is as much a threat to young children as older.
• economic this continues to be a very expensive
  vaccine

58
Vaccines in the 20th Century

• hepatitis B
• transmission percutaneous, sexual, intrapartal
  exposure almost exclusively
• historical epidemiology many current cases
  ultimately traceable to hepatitis B-contaminated
  yellow fever vaccine given to armed forces in WW
  II
• acute disease malaise, nausea, vomiting,
  jaundice, abdominal pain (1-2 fulminant with
  high mortality)
• chronic disease (especially high risk for young
  children) long, active shedding of virus, great
  risk for late cirrhosis of liver and liver cancer

59
Vaccines in the 20th Century

• Hepatitis B virus

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Vaccines in the 20th Century

• hepatitis B vaccine
• 1981 inactivated chronic-carrier serum-derived
  purified virus
• 1986 first recombinant DNA vaccine (yeast-grown
  hepatitis B surface antigen)

61
Vaccines in the 20th Century

• hepatitis A
• transmission fecal-oral, sexual
• acute disease marked malaise, nausea, vomiting,
  jaundice, abdominal discomfort (but rarely fatal)
• no chronic disease

62
Vaccines in the 20th Century

• hepatitis A vaccine
• 1995 inactivated tissue-culture grown virus

63
Vaccines in the 20th Century

• influenza (2 major types A and B)
• constantly changing genetic makeup as a result of
  easy mutation and exchange of genetic material
  (reassortment) changed virus often evades
  protection elicited by vaccines until they catch
  up with changes
• fever, sore muscles, sore throat, cough,
  headache, photophobia may predispose to serious
  secondary bacterial infections or viral
  pneumonia.
• especially dangerous for very young and very old
• sometimes major shifts in genetic makeup and
  highly virulent variants lead to deadly pandemics
  (Spanish flu) or threat of pandemic (avian flu)

64
Vaccines in the 20th Century

• influenza

65
Vaccines in the 20th Century

• influenza vaccines inactivated
• 1940s military use of inactivated vaccines
• 1950s egg-based production technology
• 1971 genetic manipulation to enable rapid
  production of vaccines tuned to cover widely
  circulating new mutations
• current 3 strains -- 2 As, 1 B -- adjusted
  each year to match genetic variants predicted to
  be in circulation
• influenza vaccines live, attenuated
  (intranasal)
• 2003 3-component egg-grown cold-adapted
  low-virulence vaccine

66
Vaccines new vaccine issues

• influenza vaccine
• present vaccine is grown in fertile chicken eggs,
  but there is a desperate need to produce a
  tissue-culture manufacturing system so a very
  quick response is possible to the emergence of
  new, dangerous strains
• also needed a vaccine administration plan that
  can accommodate a huge increase in vaccinees

67
Vaccines in the 20th Century

• rotavirus
• fecal-oral transmission very stable virus
• fever, vomiting, diarrhea, sometimes leading to
  dehydration and hospitalization frequently
  fatal in the developing world

68
Vaccines in the 20th Century

• rotavirus

69
Vaccines in the 20th Century

• rotavirus vaccines (live, oral)
• 1998 4-component rhesus-human reassortant
  vaccine
• Withdrawn 1999 on suspicion of increased risk of
  intussusception
• 2006 5-component human-bovine reassortant
  vaccine
• 2008 1-component human

70
Vaccines in the 21th Century

• human papilloma virus
• 100 different, but related, viruses mostly
  causing warts
• some strains oncogenic
• genital abnormal Pap tests, cancer of the
  cervix, vulva, vagina, anus, penis (HPV 16 and
  18)
• tonsillar and oropharyngeal cancer (HPV 16)
• some wart-producing strains with predilection for
  genital tissues
• genital warts (HPV 6 and 11)
• respiratory tract warts in infants from
  intrapartal exposure

71
Vaccines in the 21th Century

• human papilloma virus

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Vaccines in the 21th Century

• human papilloma virus vaccines
• 2006 HPV 6, 8, 16, 18 vaccine licensed
• hollow virus-like particles assembled from
  recombinant HPV viral coat proteins
• (2009? 2nd HPV 16, 18 vaccine)
• new adjuvant Al salt monophosphoryl lipid A
  (MPL)

73
Vaccines new vaccine issues

• human papillomavirus vaccine
• new vaccine (HPV 16 and 18 only) awaiting
  licensure.
• new adjuvant might give higher antibody levels
  (?longer protection but present vaccine
  protection longevity unknown)
• new adjuvant said to give more painful injections
  already a problem with HPV vaccine)
• economic present vaccine very expensive
• social/political ideally, boys ought to be
  immunized also, both to provide additional herd
  immunity and for personal protection
• social conservative resistance an issue because
  of concerns that this vaccine might decrease fear
  and increase sexual activity

74
New vaccine pros and cons

• pros
• some changes in formulation will improve outcomes
• broader coverage with additional antigens
• more antigens in combinations will decrease shots
• broader coverage with increased age range
• some social changes may improve coverage and
  vaccine acceptance
• waning of thimerosal frenzy and swine flu anxiety
• cons
• mostly, financial more vaccines and more
  expensive vaccines coinciding with difficult
  economic times
• costs often borne by families benefits accrued
  by society