Immunizations in Children and Adolescents with HIV Infection

1
Immunizations in Children and Adolescents with
HIV Infection

• Jorge Lujan-Zilbermann, M.D., M.S.
• Assistant Professor of Pediatrics
• Division of Infectious Diseases
• USF College of Medicine, Tampa, FL

2
Disclosure of Financial RelationshipsThis
speaker has the following significant financial
relationships with commercial entities to
disclose

• Research Funding
• Sanofi Pasteur
• Speakers Bureau
• GlaxoSmithKline
• MedImmune
• Merck

This slide set has been peer-reviewed to ensure
that there are no conflicts of interest
represented in the presentation.
3
Outline

• Review current recommendations for immunization
  of HIV infected children and adolescents
• Compare efficacy of available vaccines in HIV
  infected individuals
• Review new vaccines and indications in HIV
  infected patients
• Conjugate meningococcal vaccine
• Tdap
• Human papillomavirus vaccine
• Influenza
• Measles, mumps, rubella and varicella (MMRV)
• Rotavirus
• New indications for VZV vaccine in HIV-infected
  individuals

4
Principles of Vaccination

• Active Immunity
• Protection produced by the person's own immune
  system
• Usually permanent
• Passive Immunity
• Protection transferred from another person or
  animal as antibody
• Transplacental, most important source in infancy
• Temporary protection
• Potential risk for transmission of infectious
  agents

5
Live Attenuated Vaccines

• Attenuated form of the "wild type" virus or
  bacteria
• Must replicate to be effective
• Immune response similar to natural infection
• Usually effective with one dose
• Usually mild but severe reactions are possible
  occur after an incubation period (7-21 days)
• Interference from circulating antibody
• Unstable

6
Live Attenuated Vaccines

• Bacterial
• BCG
• Oral typhoid

• Viral
• Influenza (intranasal)
• Measles
• Mumps
• Polio (oral)
• Rotavirus
• Rubella
• Vaccinia
• Varicella
• Yellow fever

7
Inactivated Vaccines

• Cannot replicate
• Minimal interference from circulating antibody
• Generally not as effective as live vaccines
• Generally require 3-5 doses
• Immune response mostly humoral
• Antibody titer diminishes with time

8
Inactivated Vaccines

• Whole virus
• Polio, hepatitis A
• Bacteria
• Pertussis, cholera, typhoid
• Protein-based subunit
• Hepatitis B, influenza, acellular pertussis
• Toxoid
• Diphtheria, tetanus
• Polysaccharide-based
• Pure pneumococcal,meningococcal
• Conjugate pneumococcal, Hib, meningococcal

9
WHO
ACIP
10
Vaccines for children with HIV infection

• Vaccine Birth 1 mo 2 mo
  4 mo 6 mo 12 mo 15 mo 18 mo
  24 mo 46 y 1112 y
• Recommendations for these vaccines are the same
  as those for immunocompetent children
• Hep. B virus Hep B1 Hep B2
  Hep B3
  Hep B
• DTaP
  TDaP TDaP TDaP
  TDaP
  TDaP Tdap
• Hib
  Hib Hib
  Hib Hib
• IPV
  IPV IPV
  IPV
  IPV
• Hepatitis A virus
  
  Hep A
  Hep A
• Recommendations for these vaccines differ from
  those for immunocompetent children
• Pneumocccus
  PCV PCV PCV PCV
  PPV23 PPV23
  (57 y)
• MMR Do not administer to severely
  immunocompromised children MMR
  MMR MMR
• Varicella
  Var
  Var
  Var
• Influenza A dose is recommended every year
  starting at 6 months

11
Vaccination in HIV adults and adolescents

• Td Primary series plus booster within past 10
  years. Booster every 10 years
• Influenza (inactivated trivalent) 1 dose
  annually
• H influenzae type b (conjugate) Not routinely
  recommended
• Hepatitis A virus 2 doses All susceptible
  patients at increased risk for hepatitis A virus
  infection (eg, illegal drug users) or patients
  with chronic liver disease
• Hepatitis B virus 3 doses All susceptible
  patients (ie, antihepatitis B core antigen
  negative)
• Meningococcal (conjugate quadrivalent) Recommend
  ed
• Poliovirus (inactivated) 3 doses plus 1 booster.
  Recommended only for patients at risk
• S pneumoniae (23-valent polysaccharide) 1 dose
  (single revaccination after 5 years) CD4 count gt
  200/µL
• Varicella Contraindicated?????

12

• Direct and indirect benefits of immunization to
  the HIV-1-infected host
• Vaccines that provide herd immunity and herd
  protection (potential source of infection for HIV
  pts)
• - Oral poliovirus
• - Oral typhoid
• Oral rotavirus
• Vaccines that provide herd protection only
  (likely to indirectly benefit the HIV-infected
  host who is not immune but living in a highly
  immunized community)
• - Inactivated poliovirus
• - Diphtheria
  - Pneumococcal
• - Pertussis
  - Meningococcal
• - Measles, mumps, and rubella
  - Hepatitis A
• - Varicella
  - Hepatitis B
• Parenteral typhoid
  - BCG
• Vaccines that provide neither herd protection nor
  herd immunity (do not indirectly benefit HIV pts)
• - Tetanus - Rabies - Japanese encephalitis

13
Causes of defective antigen-specific immune
responses in HIV-infected hosts

• Defective primary immune response
• Destruction and structural and functional
  alteration of Ag-presenting cells
• Direct effect of virus on B cells
• High viremia is associated with high levels of Ag
• Non-specific hypergammaglobulinemia and failure
  of B cells to proliferate on stimulation
• Dysregulation of B cell by cytokines associated
  with HIV infection
• Defects in generation of immunologic memory
• Indirect effect of HIV-impaired T-cell help on B
  cells
• Defective capacity of B cells to differentiate in
  response to CD40 and B cell receptor trigger
• Clonal deletion/depletion of memory T and B cells

14
Pneumococcal vaccines
15
Pneumococcal Vaccine Recommendations

• Conjugate pneumococcal vaccine for children aged
  lt23 m
• Children at high risk (Functional or anatomic
  asplenia, C1, C2, C3 and C4 complement
  deficiency, chronic cardiac or pulmonary disease,
  Immunosuppression (HIV),Transplant, Chronic renal
  failure, Nephrotic syndrome, CSF leaks, DM,
  cochlear implants) who previously received PCV7
  should receive PPV23 at age gt2 years
• Children aged 24-59 months at high risk
  previously vaccinated with PPV23 should receive 2
  doses of PCV7, two months after last PPV23
• Revaccination with polysaccharide vaccine is
  recommended for persons age gt2 years at highest
  risk of serious pneumococcal infection
• Single revaccination dose gt5 years after first
  dose

16
23-valent pneumococcal polysaccharide vaccine
(Pneumovax)

• Benefits
• Immunogenic in older children and adults
• Effective against bacteremic disease
• Effective against pneumonia in young adults
• Covers 23 serotypes
• Limitations
• Does not activate T cells or prime for an
  anamnestic (memory) response. Not indicated in lt
  2 years of age. Less functional Ab
• No effect in nasal carriage
• No effect in otitis media/upper resp. tract
  infections
• Some children gt 2 yo have partial responses to
  key serotypes

17
Pnc-CRM7 Immunogenicity in US Infants, After
Primary Series
GMC, geometric mean concentrations. n 90 per
group. Controls received meningococcal C
conjugate their 7-mo mean GMC was raised from
0.02 to 0.07 ?g/mL. Pneumococcal antibody
levels after primary series of Pnc-CRM7.
Shinefield H et al. PIDJ. 199916757-63.
18
Immunogenicity of 23-valent pneumococcal vaccine
in HIV infected children

• Significant increase in specific Ig-G levels
  post-vaccination
• Patients on stable HAART had higher additional
  protection if CD4 gt25 and low viral load at
  time of vaccination

Tangsinmankong, Ann Allergy, Asthma, Immunolog
2004
19
Post-dose 3 antibody concentrations for PCV and
placebo arms in HIV infected children
Nachman, S. et al. Pediatrics 200311266-73
20
Trends in the number of cases of (IPD) in adults
with HIV infection per 100 000 persons 18 to 64
years of age living with AIDS in 7 Active
Bacterial Core surveillance areas
Flannery, B. et. al. Ann Intern Med 20061441-9
21
Difference in serotype-specific ratio of invasive
pneumococcal disease (IPD) among HIV-infected
adults per 100 000 persons living with AIDS in
2001-03 compared with baseline (1998 to 1999
average)

Change in ratio 2003-1998 All invasive disease
-19 (-29 to -7) Conjugate
serotypes -62 (-72 to
-53) Vaccine related serotypes 45
(9-72) Other non vaccine serotypes 64
(16-79) 16 serotypes in polysaccharide vaccine
only 32 (6-68)
Flannery Ann Intern Med 2006
22
Trends in the number of cases of invasive
pneumococcal disease (IPD) in adults with and
without HIV infection per 100 000 persons 18 to
64 years of age with and without AIDS for all
pneumococcal serotypes or groups of serotypes

• ? in IPD among adults with and without HIV after
  conjugate vaccine for children
• ? in IPD limited to vaccine serotypes and similar
  in adults with and without HIV infection.
• In HIV-infected adults, ? disease caused by
  serotypes not in the conjugate vaccine
  (replacement phenomenon)
• Disease caused by nonvaccine-serotype
  pneumococci ? in black men and women with HIV
  but not among white men with HIV. (Different
  exposures to children those in close contact
  with children may have had increased exposure to
  circulating nonvaccine-type strains)

Flannery. Ann Intern Med 2006.
23
Effects of conjugate pneumococcal vaccine

• Major reduction in invasive disease caused by
  vaccine serotypes in vaccinated children
• Reduction in other diseases (OM)
• Reduced rate of colonization by vaccine serotypes
  in vaccinated children
• Reduced rate of infection and colonization by
  antibiotic-resistance strains
• Reduction in disease caused by vaccine serotypes
  in nonvaccinated persons of all ages
• Increased prevalence of colonization and disease
  by nonvaccine strains (replacement)

24
DTaP and Tdap Vaccines
25
Tetanus Titers Post-vaccination
26
Incidence of Pertussis in the United States(1922
to 2003)
Hewlett, E. L. et al. N Engl J Med
20053521215-1222
27
Epidemiologic "Life cycles" of B. pertussis
before and after the use of pertussis vaccine

• Hewlett, E. N Engl J Med 20053521215-22

28
Adolescents/adults as major source of B.
pertussis infection for infants
29
DTaP Vaccines

• Purified subunit vaccine intended to reduce
  adverse reactions
• Recommended use
• Tripedia All 5 doses
• Infanrix All 5 doses of series, also 4th and 5th
  dose
• if patient received Pediarix initially
• Daptacel First 4 doses
• Approved for use in children up to 7 years of age
  

30
Tdap Vaccines

• Purified subunit vaccine, for use in
  adolescents and adults instead of tetanus and
  diphtheria toxoids (Td) vaccines
• Licensed by the FDA in 2005
• ADACEL (Sanofi Pasteur), is indicated for persons
  between 11 to 64 years of age
• BOOSTRIX (GlaxoSmithKline), is indicated for
  persons between 10 to 18 years of age

31
Tdap Vaccines Indications

• Routine vaccination for adolescents 11-18 years
  of age
• Single dose of Tdap instead of Td for booster
  immunization
• If patient has received Td, single dose of Tdap
  with a 5-year interval to avoid local or systemic
  reactions
• Vaccine should be given even if there is a
  history of pertussis disease and during pertussis
  outbreaks

32
Tdap Vaccines Indications

• Special Situations in adolescents 11-18 years of
  age
• Adolescents who require a tetanus vaccine as part
  of wound management should receive a single dose
  of Tdap instead of Td if they have not previously
  received Tdap. If previously given or not
  available patient should receive Td.

33
Tdap Vaccines Indications

• Pregnancy
• If otherwise indicated, administering Tdap to
  adolescents who are in the second or third
  trimester of pregnancy should be considered.
  Pregnancy is not a contraindication for Tdap or
  Td.
• Adults 19 years
• Adults 19-64 years of age should receive a single
  dose of Tdap for booster immunization (last Td
  gt 10 years and as soon as 2 years)
• Adults who are in close contact with an infant lt
  12 months (at least 1 month prior to contact)
• No history of DTP / DTaP / Td/ Tdap vaccination
• Series of three vaccinations, single Tdap dose,
  followed by a dose of Td 4 weeks after the
  first dose and a second dose of Td 6 months
  after the Td dose
• Health care workers

34
Tdap Vaccines Indications

• HIV infection is not a contraindication
• Follow AAP and ACIP guidelines regarding age and
  indication
• Immunogenicity in subjects with HIV has not been
  studied and could be suboptimal

35
Tdap Vaccines Contraindications

• Hypersensitivity to any component of the vaccine
• Immediate anaphylactic reaction temporally
  associated with any previous pertussis-containing
  vaccine
• Encephalopathy occurring within 7 days after
  vaccination not due attributable to another
  identifiable cause

36
Tdap Vaccines Precautions

• Moderate or severe acute illness
• If previous dose of DTP or DTaP elicited any of
  the following within 48 hours
• Temperature ? 40.5? C (105? F)
• Collapse or shock-like state (hypotonic-hyporespon
  sive episode)
• Persistent, inconsolable crying (?3 hours)
• Convulsions with or without fever occurring
  within 3 days
• Under certain circumstances, if benefit outweighs
  risk one or more additional doses may be
  considered

37
Measles, Mumps, Rubella, and Varicella Vaccines
38
Measles, Mumps, Rubella Vaccine

• Recommended and minimum age 12 months.
• If given lt 12 months should not be counted as a
  valid dose but can be used in case of outbreak
• Second dose intended to produce measles immunity
  in persons who failed to respond to the first
  dose (primary vaccine failure) and may boost
  antibody titers in some persons.
• Second dose at 4-6 years (or gt 4 wks from 1st
  dose)

39
MMR Adverse Reactions

• Fever 5-15
• Rash 5
• Joint symptoms 25
• Thrombocytopenia lt1/30,000 doses
• Parotitis rare
• Deafness rare
• Encephalopathy
  lt1/1,000,000 doses

40
MMR Vaccine Contraindications and Precautions

• Severe allergic reaction to vaccine component or
  following prior dose
• Pregnancy
• Immunosuppression not recommended for HIV
  patients with severe immunosuppression (C3) case
  of fulminant pneumonia
• Moderate or severe acute illness
• Recent blood product

41
Measles Vaccine in HIV Infection

• Severe wild-type measles in symptomatic
  HIV-infected children can lead to fatality in up
  to 40 of cases
• Measles vaccination is recommended except for
  clinical category C3

42
PPD and Measles Vaccine

• Apply PPD at same visit as MMR
• If MMR given and PPD not given at same visit,
  delay PPD by 4 weeks
• Apply PPD first - give MMR when skin test read

43
BCG and PPD

• In US, BCG is contraindicated for HIV-infected
  patients
• WHO recommends BCG in HIV infected children who
  are asymptomatic and live in areas of the world
  with a high incidence of tuberculosis
• PPD should be done yearly in HIV-infected
  patients

44
Varicella Vaccine

• Composition Live virus (Oka-Merck strain)
• Efficacy 95 (Range, 65-100)
• Duration of gt7 yearsImmunity
• Schedule 1 Dose (lt13 years of age)May be
  administered simultaneously with
  measles-mumps-rubella (MMR) vaccine
• Immunity appears to be long-lasting for most
  recipients
• Breakthrough disease much milder than in
  unvaccinated persons. Risk of breakthrough
  varicella 2.5 times higher if varicella vaccine
  administered lt30 days following MMR.No increased
  risk if varicella vaccine given simultaneously or
  gt30 days after MMR
• Risk of breakthrough infection may increase with
  time since vaccination

45
New ACIP recommendations in HIV-infected children

• Asymptomatic or mildly symptomatic HIV-infected
  children age gt 12 months with age-specific CD4
  T-cell counts gt15 and without evidence of
  varicella immunity should receive 2 doses of
  varicella vaccine 3 months apart.
• Now a second dose is recommended at 4-6 years of
  age
• Evidence of immunity
• Appropriate vaccination
• Born in US before 1966
• Hx of varicella disease (until 1997 after should
  also be laboratory confirmed)
• Hx of herpes zoster based on healthcare provider
  diagnosis
• Laboratory evidence of immunity (commercial
  assays lack sensitivity for vaccine-induced
  immunity can be used to assess disease-induced
  immunity. gpELISA or FAMA provide more sensitive
  results, but are not commercially available)

ACIP, June 2005
46
Varicella VaccineAdverse Reactions

• Injection site complaints - 20
• Rash - 3-4
• May be maculopapular rather than vesicular
• Average 5 lesions
• Systemic reactions uncommon
• Transmission of vaccine virus uncommon. Risk of
  transmission increased if vaccinee develops rash
• Asymptomatic seroconversion may occur in
  susceptible contacts
• VZIG is not recommended if a household contact
  develops rash post vaccination

47
Varicella VaccinePostexposure Prophylaxis

• Varicella vaccine is recommended for use in
  susceptible person after exposure to varicella
• 70-100 effective if given within 72 hours of
  exposure
• Not effective if gt5 days but will produce
  immunity if not infected

48
Varicella Zoster Immune Globulin (VariZIG)

• May modify or prevent disease if given lt96 hours
  after exposure
• Indications
• Immunocompromised persons
• Newborn of mothers with onset 5 days before to 2
  days after birth
• Premature infants with postnatal exposure
• Susceptible adults and pregnant women

Pneumonitis caused by VZV
Hemorrhagic varicella
49
Measles, mumps, rubella, and varicella vaccine
(MMRV)

• MMRV or ProQuad (Merck)
• Licensed by the FDA, September 6th, 2005
• Antibody response rates to VZV 6 weeks after 1
  injection of high potency MMRV (88.6) were
  similar to the response rates after concomitant
  administration of MMR and VARIVAX (93.1)
• Recipients of MMRV received a second injection of
  MMRV 90 days later.

Shinefield et al, PIDJ 200624670-5
50
Measles, mumps, rubella, and varicella vacine

• Conclusions
• One injection of MMRV resulted in antibody
  responses to the 4 vaccine components equivalent
  to those found after concomitant administration
  of MMR and VARIVAX.
• A second injection of MMRV resulted in a
  significant boost in VZV antibody.
• This boost may translate into enhanced
  immunogenicity against varicella, which is known
  to correlate with increased protection.

Shinefield et al, PIDJ 2006 24670-5
51
Hepatitis B Virus Vaccines
52
Hepatitis B Virus Vaccine

• Composition Recombinant HBsAg
• Efficacy 95 (Range,
  80-100)
• Duration of Immunity gt15 years Exposure to HBV
  results in
• 
  anamnestic anti-HBs
  response
• Schedule 3 Doses
• Booster doses not routinely recommended
• Vaccine formulations
• Recombivax HB (Merck) Engerix-B (GSK)-
  5.0 mcg/0.5 mL (pediatric)- 10 mcg/1 mL
  (adult)- 40 mcg/1 mL (dialysis) - 10 mcg/0.5
  mL (pediatric) - 20 mcg/1 mL (adult)

53
Immunogenicity of hepatitis B vaccines in
HIV-positive individuals compared with healthy
control subjects
Laurence, Am J Med 2005
54
Management of Nonresponse to Hepatitis B Vaccine

• Post vaccination serology is recommended for
• Infants born to HBsAg women
• Dialysis patients
• Immunodeficient persons
• Certain healthcare workers
• Complete a second series of three doses
• Should be given on the usual schedule of 0, 1 and
  6 months
• Retest 1 to 2 months after completing the second
  series

55
Persistent Nonresponse to Hepatitis B Vaccine

• lt5 of vaccinees do not develop anti-HBsAg after
  6 valid doses
• May be nonresponder or "hyporesponder"
• Check HBsAg status
• If exposed, treat as nonresponder with
  postexposure prophylaxis

56
Meningococcal vaccines
57
Neisseria meningitidis Risk factors for invasive
disease

• Host factors
• Terminal complement pathway deficiency
• Asplenia
• Genetic risk factors
• Exposure factors
• Household exposure
• Demographic and socioeconomic factors and
  crowding
• Concurrent upper respiratory tract infection
• Active and passive smoking

58
Meningococcal Polysaccharide Vaccine

• Menomune Quadrivalent polysaccharide vaccine (A,
  C, Y, W-135)
• Not effective in children lt18 months (except
  serotype A)
• Schedule 1 dose with revaccination in 2-5 years
  (if indicated)
• Age-related immune response
• No booster response
• Antibody with less functional activity
• Protective antibody level by 7-10 days post
  vaccination
• Consider revaccination of children first
  vaccinated when they were lt4 years of age after
  23 years if they remain at high risk. In older
  patients at risk may consider revaccination after
  3-5 years

59
Meningococcal Polysaccharide Vaccine
Recommendations

• Not recommended for routine vaccination of
  civilians.
• College students
• Control of outbreaks
• 3 or more confirmed or probable cases
• Period lt3 months
• Primary attack rate gt10 cases per 100,000
  population
• Recommended for certain high-risk persons
• Terminal complement deficiency
• Functional or anatomic asplenia
• Certain laboratory workers
• Travelers to and U.S. citizens residing in
• countries in which N. meningitidis is
  hyperendemic
• or epidemic (e.g., African meningitis belt)

60
Meningococcal polysaccharide vaccine

• Licensed in 1981, cost per dose 86.10
• Single subcutaneous dose
• Not protective in children lt 2 years of age
• Good short-term protection, 3 5 years, in older
  children
• Antibody levels decrease markedly after 2-3
  years, especially in children
• Patients at high risk need revaccination every
  3-5 years
• Adverse reactions
• Mild injection site pain, redness, and brief
  fever
• Severe allergic and neurological reactions
  lt0.1/100,000

61
Meningococcal conjugate vaccine

• Licensed in the U.S. in January 2005, cost 82
  per dose
• Approved for persons 11 55 years of age
• Likely that this vaccine or a similar one will be
  approved for use in younger age groups
• Single intramuscular dose
• Need for revaccination not yet known
• Adverse reactions similar to polysaccharide
  vaccine
• Longer duration of protection and similar
  efficacy compared to polysaccharide vaccines
  expected in adolescents

62
Attributes of conjugate meningococcal vaccine

• Broad serogroup coverage (A, C, Y, and W-135)
• Up to 83 of adolescent cases are covered by the
  vaccine
• High-quality immune response in adolescents and
  young adults
• Immunological memory induced by T cells
• Herd protection through reductions in
  nasopharyngeal carriage

63
Meningococcal conjugate vaccine Recommendations

• ACIP, Feb. 2005
• Pre-adolescent visit (11 12 years old) (now on
  hold, May 2006)
• High-school entry if not previously vaccinated
• Adolescents who wish to decrease their risk
• Groups with elevated risk of meningococcal
  disease
• College freshmen living in dormitories
• Military recruits
• Patients with complement component deficiencies
• Patients who have anatomic or functional asplenia
• Microbiologists routinely exposed to isolates of
  meningococcus
• Persons who travel or live in countries in which
  meningococcus is epidemic or hyper endemic

64
Meningococcal polysaccharide vaccine

• Recommendations for use
• Individuals at high risk ages 2 - 10 years and gt
  55
• If meningococcal conjugate vaccine is not
  available, the polysaccharide vaccine is an
  acceptable alternative for persons at elevated
  risk, ages 11 54 years

65
MCV4 and Guillain-Barre Syndrome (GBS)

• Fifteen cases of GBS reported in 17-18 years old
  patients, 2-4 weeks post MCV4 immunization
• All individuals are reported to be recovering or
  to have recovered
• More than 2.5 million doses of Menactra vaccine
  have been distributed to date. The rate of GBS
  based on the number of cases reported following
  administration of Menactra is similar to what
  might have been expected to occur by coincidence
• Pre-licensure studies conducted by Sanofi Pasteur
  of more than 7000 recipients of Menactra showed
  no GBS cases
• CDC conducted a rapid study using available
  health care organization databases and found that
  no cases of GBS have been reported to date among
  110,000 Menactra recipients

66
IMPAACT-1065

• Phase I/II randomized trial
• MCV4 vaccination to HIV infected youth between 11
  and 25 years of age
• Comparison of immunological response between one
  and two doses
• Also comparison of response by CD4 (lt15 vs.
  15)

67
Influenza Vaccines
68
Influenza vaccine composition

• 2006-07 vaccine recommended by WHO for Northern
  Hemisphere
• A/New Caledonia/20/99 (H1N1)-like virus
• A/Wisconsin/67/2005 (H3N2)-like virus
  (A/Wisconsin/67/2005 and A/Hiroshima/52/2005
  strains)
• B/Malaysia/2506/2004-like virus
  (B/Malaysia/2506/2004 and B/Ohio/1/2005 strains)

69
(No Transcript)
70
Influenza and HIV

• Risk for hospitalization was higher for
  HIV-infected women than for women with other
  high-risk conditions (chronic heart and lung
  diseases).
• Risk for influenza-related death was 9-15/10,000
  persons with AIDS compared with 0.10/10,000 among
  all persons (25-54 yrs) and 7.0/10,000 among
  persons aged gt65 years.
• Influenza symptoms might be prolonged and the
  risk for complications may be increased in
  HIV-infected persons
• Influenza vaccination produces substantial
  antibody titers (especially if high CD4 most
  effective if gt100 CD4 cells and lt30,000 viral
  copies of HIV type-1/mL .
• Advanced HIV disease and low CD4 T-lymphocyte
  cell counts, might not induce protective antibody
  titers a second dose of vaccine does not improve
  response
• HIV RNA may increase transiently in some patients
  but deterioration of CD4 or progression of HIV
  disease have not been demonstrated

71
Influenza Vaccines
72
Inactivated Influenza Vaccine Recommendations

• All persons 50 years of age or older
• Residents of long-term care facilities
• Pregnant women
• Persons 6 months to 18 years receiving chronic
  aspirin therapy or with chronic illness (asthma,
  COPD, CHF, DM , renal dysfunction,
  hemoglobinopathies, HIV, immunosuppression)
• Children gt6- 59 months of age
• Household contacts of persons 0-59 months

73
Live attenuated influenza vaccine (LAIV) in HIV
infected children (PACTG 1057)

• Design 243 HIV children 5-18 yrs with previous
  priming with inactivated influenza vaccine were
  randomized to TIV or LAIV. CD4 gt15 and VL lt
  60,000 at entry
• Results
• No unexpected toxicities or SAE
• Prolonged shedding of vaccine virus was not
  observed
• Immunologic response studies pending

Nachman, CROI 2006
74
Live Attenuated Influenza Vaccine
Contraindications and Precautions

• Children lt5 years of age
• Persons gt50 years of age
• Persons with underlying medical conditions,
  immunosuppression
• Children and adolescents receiving chronic
  aspirin therapy
• Pregnant women
• Severe (anaphylactic) allergy to egg or other
  vaccine components
• History of Guillian-Barré syndrome
• Moderate or severe acute illness

These persons should receive inactivated
influenza vaccine
75
Influenza vaccine Recommendations

• Health care workers
• High risk patients
• - Children 6 59 months of age (2006)
• - Children and teenagers on aspirin (Reyes)
• - Women in 2nd or third trimester of pregnancy
• - Persons aged 65 years or greater
• - Chronic disorders of pulmonary or
  cardiovascular systems (including asthma)

76
Influenza vaccine Recommendations

• High risk patients
• Metabolic diseases (including diabetes), renal
  dysfunction, hemoglobinopathies
• Immunosuppression requiring regular follow-up or
  hospitalization in the last year
• Persons with any condition (e.g., cognitive
  dysfunction, spinal cord injuries, seizure
  disorders or other neuromuscular disorders) that
  can compromise respiratory function or the
  handling of respiratory secretions or that can
  increase the risk of aspiration should be
  vaccinated against influenza (2005
  recommendation)

77
Intranasal influenza vaccine

• Trivalent (same strains as inactivated vaccine),
  live, attenuated influenza vaccine administered
  as a nasal spray (Flumist)
• HA and NA from desired strains are reassorted
  onto a master background from a cold attenuated
  strain
• 86 to 93 effective in preventing culture-proven
  influenza in children 15 months to 6 years old
  (better than historical data for inactivated
  vaccine) even in a year where there was a poor
  match to the circulating strain
• Approved by FDA in 2003, however it is only
  indicated for healthy patients between ages of 5
  - 49 years

78
Human Papilloma Virus Vaccines
79
Human papillomavirus Epidemiology

• Most common sexually transmitted disease in U.S.
• Highest prevalence among sexually active
  adolescents and young adults (15-24 years of age)
• 40 of sexually active adolescent girls have been
  infected
• Median age of first intercourse in U.S. is 15
  years
• Infection occurs within 2 years of sexual debut
• 30 HPV types produce genital infection, most
  infections are asymptomatic and resolve
• Infection with types 6 and 11 causes anogenital
  warts 16 and 18 cause cervical dysplasia
• Cervical involvement is common and often
  associated with the development of transient
  cervical cytologic abnormalities
• HSIL progresses to invasive cervical cancer over
  10 15 years

80
Human papillomavirus Epidemiology

• HPV is the cause of all cervical cancer and most
  anogenital cancers in women and men
• Two high-risk serotypes, 16 and 18, are
  responsible for up to 70 of cervical cancer
  cases
• Cervical cancer
• Despite screening programs, still 10,000
  cases/year
• 3,700 deaths/year from complications
• Higher incidence is non-white racial/ethnic
  groups, lower socioeconomic groups, foreign-born
  women, and in the South

81
HPV and HIV

• REACH cohort 40 HIV infected vs. 10 controls
  had persistent HPV infection
• In HIV patients with LSIL, 30 progressed to
  HSIL within 36 months
• Recurrences occur in 60 of HIV at 3 years.
• Increase risk for penile and anal cancer in HIV
  males

82
HPV Vaccines

• Gardasil (Merck)
• Quadrivalent vaccine serotypes 6,11, 16 and 18
• Licensed by FDA in 2006
• Cervarix (GlaxoSmithKline)
• Bivalent vaccine serotypes 16 and 18
• Pending FDA License
• Both vaccines require 3 doses over 6 months
• Well-tolerated and no significant adverse events

83
HPV Vaccines

• Both vaccines are made of the major viral outer
  capside protein of each of the included HPV types
• Viral capsid protein can be made to self-assemble
  into a highly purified, empty, virus-like
  particle (VLP) that mimics natural HPV
• VLPs induce type-specific neutralizing
  antibodies that are very protective with no
  oncogenic potential

84
HPV and HIV infected children

• PACTG 1047
• Quadrivalent HPV vaccine in 3 dose schedule
• HIV infected children between 7 and 11 years of
  age
• 120 children enrolled in fall 2006
• Safety and efficacy results pending

85
Rotavirus vaccine
86
Rotavirus - Epidemiology

• Most common cause of severe diarrhea in infants
  and young children worldwide
• Nearly all children infected by age 5 years
• U.S. 500,000 office visits / year
• 55,000 hospitalizations/ year and 20 40
  deaths/year
• Worldwide 600,000 850,000 deaths / year

87
Rotavirus Vaccine

• Rotateq (Merck)
• Approved by FDA, Feb 2006
• Pentavalent vaccine with specificity against five
  human serotypes G 1 4, and P1
• All serotypes are human bovine reassortants
• Three doses at 2, 4, and 6 months of age (first
  dose between 6 to 12 weeks last dose by 32 weeks
  of age)
• Oral vaccine that does not require feeding or
  administration of buffer before dosing to
  neutralize stomach acid

88
Rotavirus vaccine

• Well tolerated with respect to intussusception
  and other adverse experiences
• Good immunogenicity
• Efficacious against rotavirus gastroenteritis of
  any severity and highly efficacious against
  severe disease
• Can be administered concomitantly with other
  license pediatric vaccines on the same
  immunization schedule

89
Rotavirus Vaccine Contraindications and
Precautions

• Severe allergic reaction (C)
• Acute gastroenteritis (P)
• Moderate to Severe Illness (P)
• Preexisting chronic gastrointestinal disease (P)
• Intussusception (P)
• Altered immunocompetence (no data on HIV infected
  or exposed children) (P)

90
Rotavirus Vaccine

• Infants living in households with persons who
  have or are suspected of having an
  immunodeficiency disorder, including HIV
  infection, can be vaccinated
• Good hand washing precautions after contact with
  feces of vaccinated infant is highly recommended

91
Hepatitis A Virus Vaccines
92
Hepatitis A Virus Vaccines

• Two vaccines available
• VAQTA (Merck)
• HAVRIX (GlaxoSmithKline)
• Now approved and recommended for use in children
  12 months of age
• Epidemiology
• Hepatitis A virus infection rates in US have
  dropped by 76
• Declines greatest among children 2-18 years of
  age (87)
• Rate from 9.2/100,000 in 1983 to 2.6/100,000 in
  2003

Wasley et al, JAMA 2005294194-201
93
Hepatitis A Virus Vaccines Indications

• All children at age 1 year
• MSM
• Users of injection and noninjection drugs
• Travelers to high or intermediate endemic areas
• Occupational risk (infected primates, HAV
  research)
• Persons with clotting-factor disorders
• Persons with chronic liver disease
• Outbreaks

94
Hepatitis A Virus Vaccine in HIV infected children

• PACTG 1008 Protocol
• 235 children with CD4 20 received 2 vaccine
  doses 24 weeks apart
• 117 children received a third dose after 104
  weeks
• Better response to the vaccine if they had
  undetectable HIV RNA

Weinberg A et al. JID 2006193302-11
95
Hepatitis A Virus Vaccine in HIV infected children

• Standard 2-dose regimen generated low antibody
  titers, 97 response at 32 weeks, and 90
  response at 104 weeks
• A third vaccine dose was safe and increased the
  antibody titers, suggesting that an increase in
  immunizations may be warranted in this population

Weinberg A et al. JID 2006193302-11
96
Summary

• Most immunizations as recommended by AAP and ACIP
• Response might be suboptimal in HIV infected
  subjects
• Evaluation necessary to determine need for extra
  doses
• Ongoing trials should provide information about
  LAIV, HPV, and MCV4 in HIV-infected children and
  adolescents