Immunizations in Children and Adolescents with HIV Infection: 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


Disclosure of Financial RelationshipsThis speaker has the following significant financial relationships with commercial entities to disclose:: Disclosure of Financial Relationships This speaker has the following significant financial relationships with commercial entities to disclose: Research Funding: Sanofi Pasteur Speaker’s Bureau: GlaxoSmithKline MedImmune Merck This slide set has been peer-reviewed to ensure that there are no conflicts of interest represented in the presentation.


Outline: 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


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 Principles of Vaccination


Live Attenuated Vaccines: 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


Live Attenuated Vaccines: Live Attenuated Vaccines Viral: Influenza (intranasal) Measles Mumps Polio (oral) Rotavirus Rubella Vaccinia Varicella Yellow fever Bacterial: BCG Oral typhoid


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 Inactivated Vaccines


Inactivated Vaccines: 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


Slide9: WHO ACIP


Vaccines for children with HIV infection: Vaccines for children with HIV infection Vaccine Birth 1 mo 2 mo 4 mo 6 mo 12 mo 15 mo 18 mo 24 mo 4–6 y 11–12 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 (5–7 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


Vaccination in HIV adults and adolescents: 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) — Recommended 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 > 200/μL Varicella — Contraindicated?????


Slide12: 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


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


Pneumococcal vaccines: Pneumococcal vaccines


Pneumococcal Vaccine Recommendations: Conjugate pneumococcal vaccine for children aged 2 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 >2 years at highest risk of serious pneumococcal infection Single revaccination dose >5 years after first dose Pneumococcal Vaccine Recommendations


23-valent pneumococcal polysaccharide vaccine (Pneumovax): 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 2 yo have partial responses to key serotypes


Pnc-CRM7: Immunogenicity in US Infants, After Primary Series: 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. 1999;16:757-63.


Immunogenicity of 23-valent pneumococcal vaccine in HIV infected children: 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% >25% and low viral load at time of vaccination Tangsinmankong, Ann Allergy, Asthma, Immunolog 2004


Slide19: Nachman, S. et al. Pediatrics 2003;112:66-73 Post-dose 3 antibody concentrations for PCV and placebo arms in HIV infected children


Slide20: Flannery, B. et. al. Ann Intern Med 2006;144:1-9 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


Slide21: Flannery Ann Intern Med 2006 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)


Slide22: Flannery. Ann Intern Med 2006. 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)


Effects of conjugate pneumococcal vaccine: 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)


DTaP and Tdap Vaccines: DTaP and Tdap Vaccines


Tetanus Titers Post-vaccination: Tetanus Titers Post-vaccination


Slide26: Hewlett, E. L. et al. N Engl J Med 2005;352:1215-1222 Incidence of Pertussis in the United States (1922 to 2003)


Slide27: Epidemiologic "Life cycles" of B. pertussis before and after the use of pertussis vaccine Hewlett, E. N Engl J Med 2005;352:1215-22


Adolescents/adults as major source  of B. pertussis infection for infants: Adolescents/adults as major source of B. pertussis infection for infants


DTaP Vaccines: 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


Tdap Vaccines: 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


Tdap Vaccines: Indications: 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


Tdap Vaccines: Indications: 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.


Tdap Vaccines: Indications: 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 > 10 years and as soon as 2 years) Adults who are in close contact with an infant < 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


Tdap Vaccines: Indications: 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


Tdap Vaccines: Contraindications : 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


Tdap Vaccines: Precautions: 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-hyporesponsive 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


Measles, Mumps, Rubella, and Varicella Vaccines : Measles, Mumps, Rubella, and Varicella Vaccines


Measles, Mumps, Rubella Vaccine: Recommended and minimum age: 12 months. If given 4 wks from 1st dose) Measles, Mumps, Rubella Vaccine


MMR Adverse Reactions: MMR Adverse Reactions Fever 5%-15% Rash 5% Joint symptoms 25% Thrombocytopenia <1/30,000 doses Parotitis rare Deafness rare Encephalopathy <1/1,000,000 doses


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 MMR Vaccine: Contraindications and Precautions


Measles Vaccine in HIV Infection: 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


PPD and Measles Vaccine: 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


BCG and PPD: 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


Varicella Vaccine: Varicella Vaccine Composition Live virus (Oka-Merck strain) Efficacy 95% (Range, 65%-100%) Duration of >7 years Immunity Schedule 1 Dose (30 days after MMR Risk of breakthrough infection may increase with time since vaccination


New ACIP recommendations in HIV-infected children: New ACIP recommendations in HIV-infected children Asymptomatic or mildly symptomatic HIV-infected children age > 12 months with age-specific CD4 T-cell counts >15% 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


Varicella Vaccine:Adverse Reactions: Varicella Vaccine: Adverse 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


Varicella VaccinePostexposure Prophylaxis: Varicella Vaccine Postexposure 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 >5 days but will produce immunity if not infected


Varicella Zoster Immune Globulin (VariZIG): Varicella Zoster Immune Globulin (VariZIG) May modify or prevent disease if given <96 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


Measles, mumps, rubella, and varicella vaccine (MMRV): 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 2006;24:670-5


Measles, mumps, rubella, and varicella vacine : 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 ;24:670-5


Hepatitis B Virus Vaccines: Hepatitis B Virus Vaccines


Hepatitis B Virus Vaccine: Hepatitis B Virus Vaccine Composition: Recombinant HBsAg Efficacy 95% (Range, 80%-100%) Duration of Immunity >15 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)


Slide53: Immunogenicity of hepatitis B vaccines in HIV-positive individuals compared with healthy control subjects Laurence, Am J Med 2005


Management of Nonresponse to Hepatitis B Vaccine: 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


Persistent Nonresponse to Hepatitis B Vaccine: Persistent Nonresponse to Hepatitis B Vaccine <5% 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


Meningococcal vaccines: Meningococcal vaccines


Neisseria meningitidis Risk factors for invasive disease: 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


Meningococcal Polysaccharide Vaccine: Meningococcal Polysaccharide Vaccine Menomune: Quadrivalent polysaccharide vaccine (A, C, Y, W-135) Not effective in children <18 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 <4 years of age after 2–3 years if they remain at high risk. In older patients at risk may consider revaccination after 3-5 years


Meningococcal Polysaccharide Vaccine: Recommendations: Meningococcal Polysaccharide Vaccine: Recommendations Not recommended for routine vaccination of civilians. College students Control of outbreaks: 3 or more confirmed or probable cases Period 10 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)


Meningococcal polysaccharide vaccine: Meningococcal polysaccharide vaccine Licensed in 1981, cost per dose $86.10 Single subcutaneous dose Not protective in children < 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 <0.1/100,000


Meningococcal conjugate vaccine: 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


Attributes of conjugate meningococcal vaccine: 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


Meningococcal conjugate vaccine: Recommendations: 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


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


MCV4 and Guillain-Barre Syndrome (GBS): 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


IMPAACT-1065: 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% (<15% vs. ≥15%)


Influenza Vaccines: Influenza Vaccines


Influenza vaccine composition: 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)


Influenza and HIV: 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 >65 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 >100 CD4+ cells and <30,000 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


Influenza Vaccines: Influenza Vaccines


Inactivated Influenza Vaccine Recommendations: 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 >6- 59 months of age Household contacts of persons 0-59 months


Live attenuated influenza vaccine (LAIV) in HIV infected children (PACTG 1057): 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% >15% and VL < 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


Live Attenuated Influenza Vaccine: Contraindications and Precautions: Children 50 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 Live Attenuated Influenza Vaccine: Contraindications and Precautions *These persons should receive inactivated influenza vaccine


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


Influenza vaccine: Recommendations: 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)


Intranasal influenza vaccine: 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


Human Papilloma Virus Vaccines: Human Papilloma Virus Vaccines


Human papillomavirus: Epidemiology: 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


Human papillomavirus: Epidemiology: 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


HPV and HIV: 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


HPV Vaccines: 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


HPV Vaccines: 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 VLP’s induce type-specific neutralizing antibodies that are very protective with no oncogenic potential


HPV and HIV infected children: 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


Rotavirus vaccine: Rotavirus vaccine


Rotavirus - Epidemiology: 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


Rotavirus Vaccine: 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


Rotavirus vaccine: 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


Rotavirus Vaccine: Contraindications and Precautions: 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)


Rotavirus Vaccine: 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


Hepatitis A Virus Vaccines: Hepatitis A Virus Vaccines


Hepatitis A Virus Vaccines: 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 2005;294:194-201


Hepatitis A Virus Vaccines: Indications: 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


Hepatitis A Virus Vaccine in HIV infected children: 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 2006;193:302-11


Hepatitis A Virus Vaccine in HIV infected children: 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 2006;193:302-11


Summary: 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