Influenza Vaccine in HIV Infected Children
Condition: Influenza With Pneumonia, Influenza Virus Identified
MeSH terms: Influenza, Human
Study type: Interventional
Phase: Phase 4

Summary: 
      Influenza associated pneumonia causes significant morbidity in young HIV-infected children.
      Although annual vaccination against influenza is recommended for HIV infected children, it
      has not been implemented as routine care, due to the lack of data on disease burden and
      vaccine efficacy.

      This study aims at determining the effectiveness of influenza vaccination in HIV infected
      children in South Africa.
    

Detailed description: 
      Influenza virus infects 30 to 50% of children under five years of age during the course of
      any epidemic. The attack rates of influenza virus associated illness during infancy remains
      high, and at least 50% of influenza associated hospitalisation amongst children occurs in
      infants <6 months of age. Approximately 33% of children would have been infected at least
      once during their first year of life. The estimated attack rates in children aged 0-5 and
      6-12 months for influenza illness is 12.4/100 and 20.3/100 child years respectively.
      Influenza virus causes LRTI amongst 89% of children infected in the 6-12 month age group. The
      risk of influenza infection is higher amongst older children (2-5 years of age); however, the
      risk of developing LRTI (78 versus 2.5 per 100 child years) is greater amongst younger
      children (< 2 years of age).

      In South Africa, the burden of influenza associated pneumonia has been characterized in HIV
      infected children. The incidence of severe pneumonia in which influenza virus was identified
      was 8.03 fold (95%CI 5.05-12.76) greater in HIV infected compared to HIV non-infected
      children (1 268 versus 148 per 100 000 child years) aged < 2 years. These rates however
      provide a very conservative estimate as to the burden of influenza illness, since it excludes
      children with influenza illness that were hospitalized for syndromes other than pneumonia as
      well as children managed as outpatients. Furthermore, although the duration of
      hospitalization for influenza associated pneumonia was similar between HIV infected and HIV
      uninfected children (median 4-5 days), there was a statistically non-significant increased
      risk of mortality among HIV infected children (8.0% versus 2.2%; P=0.20). Much of the
      differences in morbidity and mortality in HIV infected individuals with influenza-associated
      pneumonia may be due to contribution of other co-existing pathogens.

      Recommendations made by the Advisory Committee on Immunization Practices (ACIP) advocating
      the annual use of the subunit influenza vaccine in HIV-1 infected children are largely
      founded on the theoretical concern regarding the potential severity of influenza disease in
      HIV-1 infected children. Although vaccination with the subunit influenza vaccine is
      recommended for HIV-1 infected children >6 months of age, there are concerns regarding the
      benefits of vaccination in these children. These include that in addition to a poor immune
      response to the vaccine, particularly in severely immunocompromised HIV-1 infected children,
      increases in plasma HIV RNA following vaccination have been described. The increase in plasma
      HIV RNA was transient and does not appear to be of any long-term clinical significance.
      Recently a few studies, with partly conflicting results, have been undertaken evaluating the
      immunogenicity of influenza vaccination in children on antiretroviral therapy. However, no
      such studies have been undertaken in Africa or Asia where the burden of paediatric HIV is the
      greatest.

      The routine use of influenza vaccine in HIV infected children remains low, partly related to
      the lack of adequate data regarding the burden of influenza associated disease in these
      children as well as the lack on any vaccine-efficacy data in HIV infected children.
      Determining the burden of disease and effectiveness of influenza vaccine in HIV infected
      children will have a bearing on routine immunization recommendations as well as planning for
      future influenza pandemics.

      Differences in the epidemiology of HIV between developing and developed countries in which
      the prevalence of HIV is low to that of high-burden sub-Saharan African countries makes it
      necessary to be cautious in extrapolating data and recommendations of developed countries to
      developing countries. These differences may include: i. differences in standard of care,
      including access to prophylaxis against opportunistic infections and use of highly active
      anti-retroviral therapy (HAART); ii. differences in risk for disease from opportunistic
      pathogens, e.g. Mycobacterium tuberculosis, etc. These differences may all contribute to
      differences in the risk and severity of influenza illness among HIV infected individuals from
      these communities as well as possibly responsiveness and effectiveness of vaccination.

      It is within this context that this study aims at determining the effectiveness of influenza
      vaccination in HIV infected children in South Africa. The significance of the findings from
      this study will help quantify the burden of influenza illness in African HIV infected
      children, in the era of HAART, as well as assist in making more informed recommendations for
      the use of influenza vaccine in HIV infected children and in guiding national policy for
      preparing for a future influenza virus-pandemic.

      350 Patients will be recruited at Chris Hani-Baragwanath Hospital, Soweto, South Africa onto
      this prospective, double-blind, placebo randomised controlled trial evaluating the efficacy
      of a tri-valent sub-unit influenza vaccine in HIV infected children. Participants will be
      randomized to receive either two doses of Influenza sub-unit vaccine or placebo one month
      apart, preceding the 2009 Influenza season. 100 children will be included into the
      immunogenicity cohort, and have blood drawn to evaluate baseline influenza strain specific
      antibody levels and subsequent levels one-month following the first and second doses of study
      vaccine.

      Study participants will be followed up during the course of the influenza season, which will
      be defined as starting 1st May 2009 and ending 30th September 2009. Subjects will be
      contacted weekly to determine whether they fulfill the criteria for Influenza-like illness.
      Subjects who fulfill the criteria for diagnosing ILI will be requested to come into the
      clinic within 48 hours for further investigation, which will involve a nasopharyngeal
      aspirate (for identification of respiratory viruses), nasopharyngeal swab (for identification
      of Streptococcus pneumoniae colonization) and blood draw (for culture and Streptococcus
      pneumoniae testing).
    

Intervention name(s): Trivalent sub-unit influenza vaccine; Saline, 0.5ml
Intervention type(s): Biological; Biological
Intervention description(s): Composition per 0.5 ml dose:
Active substance:
Split Influenza virus*, inactivated Strains for 2009 Southern hemisphere A/Brisbane/59/2007- like (H1N1) 15 micrograms**, A/Brisbane/10/2007 (H3N2) - like strain (A/Brisbane/10/2007 (IVR-147) 15 micrograms**, B/Florida/4/2006 - like strain (B/Brisbane/3/2007)15 micrograms** Two doses, one month apart; Saline IMI, 0.5ml. Two doses one month apart
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Viral-confirmed