Clare L. Cutland

Influenza vaccination of pregnant women and protection of their infants.

BACKGROUND There are limited data on the efficacy of vaccination against confirmed influenza in pregnant women with and those without human immunodeficiency virus (HIV) infection and protection of their infants. METHODS We conducted two double-blind, randomized, placebo-controlled trials of trivalent inactivated influenza vaccine (IIV3) in South Africa during 2011 in pregnant women infected with HIV and during 2011 and 2012 in pregnant women who were not infected. The immunogenicity, safety, and efficacy of IIV3 in pregnant women and their infants were evaluated until 24 weeks after birth. Immune responses were measured with a hemagglutination inhibition (HAI) assay, and influenza was diagnosed by means of reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assays of respiratory samples. RESULTS The study cohorts included 2116 pregnant women who were not infected with HIV and 194 pregnant women who were infected with HIV. At 1 month after vaccination, seroconversion rates and the proportion of participants with HAI titers of 1:40 or more were higher among IIV3 recipients than among placebo recipients in both cohorts. Newborns of IIV3 recipients also had higher HAI titers than newborns of placebo recipients. The attack rate for RT-PCR-confirmed influenza among both HIV-uninfected placebo recipients and their infants was 3.6%. The attack rates among HIV-uninfected IIV3 recipients and their infants were 1.8% and 1.9%, respectively, and the respective vaccine-efficacy rates were 50.4% (95% confidence interval [CI], 14.5 to 71.2) and 48.8% (95% CI, 11.6 to 70.4). Among HIV-infected women, the attack rate for placebo recipients was 17.0% and the rate for IIV3 recipients was 7.0%; the vaccine-efficacy rate for these IIV3 recipients was 57.7% (95% CI, 0.2 to 82.1). CONCLUSIONS Influenza vaccine was immunogenic in HIV-uninfected and HIV-infected pregnant women and provided partial protection against confirmed influenza in both groups of women and in infants who were not exposed to HIV. (Funded by the Bill and Melinda Gates Foundation and others; ClinicalTrials.gov numbers, NCT01306669 and NCT01306682.).

The Impact of a 9-Valent Pneumococcal Conjugate Vaccine on the Public Health Burden of Pneumonia in HIV-Infected and -Uninfected Children

INTRODUCTION Pneumococcal conjugate vaccine (PnCV) may be used as a probe to define the burden of pneumococcal disease and better characterize the clinical presentation of pneumococcal pneumonia. METHODS This study used a 9-valent PnCV to define different end points of vaccine efficacy and the preventable burden of pneumococcal pneumonia in 39,836 children who were randomized in a double-blind, placebo-controlled trial in South Africa. RESULTS Whereas the point-estimate of vaccine efficacy was greatest when measured against the outcome of vaccine-serotype specific pneumococcal bacteremic pneumonia (61%; P = .01), the sensitivity of blood culture to measure the burden of pneumococcal pneumonia prevented by vaccination was only 2.6% in human immunodeficiency virus (HIV)-uninfected children and 18.8% in HIV-infected children. Only 37.8% of cases of pneumococcal pneumonia prevented by PnCV were detected by means of chest radiographs showing alveolar consolidation. A clinical diagnosis of pneumonia provided the best estimate of the burden of pneumococcal pneumonia prevented through vaccination in HIV-uninfected children (267 cases prevented per 100,000 child-years) and HIV-infected children (2573 cases prevented per 100,000 child-years). CONCLUSION Although outcome measures with high specificity, such as bacteremic pneumococcal pneumonia, provide a better estimate as to vaccine efficacy, the burden of disease prevented by vaccination is best evaluated using outcome measures with high sensitivity, such as a clinical diagnosis of pneumonia.

Long-Term Effect of Pneumococcal Conjugate Vaccine on Nasopharyngeal Colonization by Streptococcus pneumoniae—and Associated Interactions with Staphylococcus aureus and Haemophilus influenzae Colonization—in HIV-Infected and HIV-Uninfected Children

After a primary series of 3 doses, it was found that a 9-valent pneumococcal conjugate vaccine no longer reduces nasopharyngeal colonization by vaccine serotypes in children 5.3 years of age. In addition, human immunodeficiency virus (HIV)-infected children (n=81) had a higher prevalence of colonization by Streptococcus pneumoniae and Haemophilus influenzae (71.6% and 74.1%, respectively) than did HIV-uninfected children (n=271; 50.9% and 52.0%, respectively), suggesting that increased colonization may contribute to the greater burden of pneumococcal disease in HIV-infected children. Inverse associations between colonization by S. pneumoniae and colonization by Staphylococcus aureus and between colonization by S. aureus and colonization by H. influenzae were observed only in HIV-uninfected children, possibly as a result of suboptimal adaptive immunity after previous colonization in HIV-infected children.

Pneumococcal Coinfection with Human Metapneumovirus

BACKGROUND Infection with the newly discovered human metapneumovirus (hMPV) may lead to hospitalization of children with lower respiratory tract infection (LRTI), although the pathogenesis thereof remains to be elucidated. METHODS This hypothesis-generating study involved a cohort of children randomized to receive 9-valent conjugate pneumococcal vaccine or placebo and who were tested for hMPV infection when hospitalized for LRTI. By use of a nested reverse-transcription polymerase chain reaction assay targeted at amplifying a fragment of the hMPV fusion (F) protein gene, 202 such infections were identified among 2715 episodes of LRTI in children. RESULTS Among human immunodeficiency virus (HIV)-uninfected children who had received 3 doses of conjugate pneumococcal vaccine, the incidence of hMPV-associated LRTI was reduced by 45% (95% confidence interval [CI], 19%-62%; P = .002), and the incidence of clinical pneumonia was reduced by 55% (95% CI, 22%-74%; P = .003). Similarly, in fully vaccinated HIV-infected children, the incidence of hMPV-associated LRTI was reduced by 53% (95% CI, 3%-77%; P = .035), and that of clinical pneumonia was reduced by 65% (95% CI, 19%-85%; P = .020). CONCLUSIONS The pathogenesis of hMPV-associated LRTI that results in hospitalization of both HIV-infected and -uninfected children involves bacterial coinfection with pneumococcus, and a significant proportion of these hospitalizations may be prevented by vaccination with pneumococcal conjugate vaccine.

Quantitative and qualitative antibody response to pneumococcal conjugate vaccine among African human immunodeficiency virus-infected and uninfected children.

Objective: To determine the quantitative and qualitative antibody responses to a pneumococcal conjugate vaccine (PnCV) in human immunodeficiency virus (HIV)-exposed infected and uninfected children. Methods: Children were randomized to receive either a PnCV or placebo at 6, 10 and 14 weeks of age. PnCV serotype-specific antibody concentrations were measured by a standard enzyme immunoassay (EIA) and a 22F modified EIA (22F EIA) on single serum samples drawn at 21–42 days post-dose 3. Functional activities of the serotype-specific antibody to serotypes 6B, 19F and 23F were measured with an opsonophagocytic assay (OPA). Results: The geometric mean antibody concentrations (GMC) were similar in HIV-infected and HIV-uninfected PnCV recipients for 7 of the 9 vaccine serotypes. In placebo recipients, the GMCs were significantly higher in HIV-infected than in uninfected children for 7 of the serotypes. In HIV-infected PnCV recipients, the GMCs were lower for 5 of the serotypes in children with severe acquired immunodeficiency syndrome than in children who were asymptomatic or mildly symptomatic with acquired immunodeficiency syndrome. HIV-infected PnCV recipients were less likely to have measurable functional antibody (OPA titer ≥1/8) to all 3 studied serotypes (6B, 19F and 23F) than in HIV-uninfected children. HIV-infected children required a higher concentration of anticapsular antibody to achieve 50% of the maximum uptake of labeled Streptococcus pneumoniae in the OPA assay than HIV-uninfected children for 2 of the 3 serotypes, although this was significant only for serotype 6B (P = 0.0005). Conclusion: HIV-infected children have similar quantitative antibody responses but poorer qualitative antibody responses to the PnCV.

The Interferon Antagonist NS2 Protein of Respiratory Syncytial Virus Is an Important Virulence Determinant for Humans

BACKGROUND Respiratory syncytial virus (RSV) is targeted for vaccine development, because it causes severe respiratory tract illness in the elderly, young children, and infants. A primary strategy has been to derive live attenuated viruses for use in intranasally administered vaccines that will induce a protective immune response. In the present study, the NS2 gene, whose encoded protein antagonizes the hosts interferon- alpha / beta response, was deleted from RSV vaccine candidates by use of reverse genetics. METHODS Three NS2 gene-deleted RSV vaccine candidates were studied: rA2cp Delta NS2, rA2cp248/404 Delta NS2, and rA2cp530/1009 Delta NS2. rA2cp Delta NS2, which had the fewest attenuating mutations, was evaluated in adults and RSV-seropositive children. rA2cp248/404 Delta NS2 and rA2cp530/1009 Delta NS2 were evaluated in adults and RSV-seropositive and RSV-seronegative children. RESULTS At a high dose (10(7.0) pfu), rA2cp Delta NS2 was not shed by adults, and only 13% of them had an immune response. The other vaccine candidates, rA2cp248/404 Delta NS2 and rA2cp530/1009 Delta NS2, had greatly decreased infectivity in RSV-seronegative children, compared with that of their immediate parent strains, which possess an intact NS2 gene. CONCLUSIONS Deletion of the NS2 gene attenuates RSV in subjects of all ages studied. This validates the strategy of developing live respiratory tract virus vaccines in which the viruss ability to inhibit the human innate immune system is blocked. rA2cp248/404 Delta NS2 should be studied in children at a higher input titer, because it was more infectious and immunogenic than was rA2cp530/1009 Delta NS2.

Trivalent Inactivated Influenza Vaccine in African Adults Infected With Human Immunodeficient Virus: Double Blind, Randomized Clinical Trial of Efficacy, Immunogenicity, and Safety

BACKGROUND Data on the efficacy of trivalent, inactivated influenza vaccine (TIV) in HIV-infected adults, particularly in Africa, are limited. This study evaluated the safety, immunogenicity, and efficacy of TIV in HIV-infected adults. METHODS In Johannesburg, South Africa, we undertook a randomized, double-blind, placebo-controlled trial involving 506 HIV-infected adults. Subjects included 157 individuals who were antiretroviral treatment (ART) naive and 349 on stable-ART. Participants were randomly assigned to receive TIV or normal saline intramuscularly. Oropharyngeal swabs were obtained at illness visits during the influenza season and tested by shell vial culture and RT PCR assay for influenza virus. Immune response was evaluated by hemagglutinin antibody inhibition assay (HAI) in a nested cohort. The primary study outcome involved vaccine efficacy against influenza confirmed illness. This trial is registered with ClinicalTrials.gov, number NCT00757900. RESULTS The efficacy of TIV against confirmed influenza illness was 75.5% (95% CI: 9.2%-95.6%); with a risk difference of 0.18 per 100 person-weeks in TIV recipients. Among TIV recipients, seroconversion, measured by HAI titers, was evident in 52.6% for H1N1, 60.8% for H3N2, and 53.6% for influenza B virus. This compared with 2.2%, 2.2%, and 4.4% of placebo recipients (P < .0001). The frequency of local and systemic adverse events post-immunization was similar between study groups. CONCLUSIONS TIV immunization is safe and efficacious in African HIV-infected adults without underlying co-morbidities. Further evaluation of effectiveness is warranted in severely immunocompromized HIV-infected adults and those with co-morbidities such as tuberculosis.

Ineffectiveness of Trimethoprim-Sulfamethoxazole Prophylaxis and the Importance of Bacterial and Viral Coinfections in African Children with Pneumocystis carinii Pneumonia

African human immunodeficiency virus type 1 (HIV-1)-infected children were evaluated to define the burden of Pneumocystis carinii pneumonia (PCP) and its interaction with bacterial and viral pathogens. P. carinii was identified in 101 (43.7%) of 231 episodes of pneumonia among 185 HIV-1-infected children (median age, 4.5 months; range, 1.7-27.3 months). Receipt of trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis was not associated with a significant reduction (36%; 95% confidence interval [CI], -15.4% to 64.5%) in isolation of P. carinii among children considered to have received adequate prophylaxis (37.7% of children) compared with children who had never received any prophylaxis (48.5% of children). However, deaths among children with PCP who had been taking TMP-SMX prophylaxis were markedly reduced (98.6%; 95% CI, 89.1%-99.8%) compared with children who were not taking prophylaxis. Concurrent P. carinii infection was observed in 6 of 18, 11 of 26, and 4 of 6 HIV-1-infected children who had bacteremia, a respiratory virus isolated, or Mycobacterium species isolated, respectively.

Seasonality, incidence, and repeat human metapneumovirus lower respiratory tract infections in an area with a high prevalence of human immunodeficiency virus type-1 infection.

Background: There is limited information regarding the epidemiology of human metapneumovirus (hMPV) from Africa, despite it being identified as a common pathogen in children with pneumonia. Objectives: Determine the epidemiology of severe hMPV-associated lower respiratory tract infection (LRTI) in human immunodeficiency virus type-1 (HIV) infected and uninfected children. Methods: Nasopharyngeal aspirate samples from children hospitalized for LRTI between January 2000 and December 2002 were analyzed for common respiratory viruses using an immunfluorescence assay; and 2715 available nasopharyngeal aspirate samples were tested for hMPV by reverse-transcriptase polymerase chain reaction targeting its fusion protein. Phylogenetic analysis of the fusion (F) gene was performed on samples associated with repeat hMPV infections in the same child. Results: hMPV was identified perennially and was the second most commonly identified respiratory virus (11.3% versus 21.1% for respiratory syncytial virus, P < 0.0001) in HIV-uninfected children. The burden of hospitalization for hMPV-LRTI was 5.4 (95% CI: 3.5–7.5) fold greater in HIV-infected (2935 per 100,000) compared with HIV-uninfected children [575 (95% CI: 472–695) per 100,000]. HIV-infected children had greater evidence of bacterial coinfection and a higher mortality rate than did uninfected children. Repeat hMPV associated hospitalizations involved homologous (B2 subgroup) and heterologous (A1 and B2) hMPV. Conclusions: There is a high burden of hMPV-LRTI and repeat severe infections occur from homologous and heterologous subgroups of the virus.

Quantitative and Qualitative Anamnestic Immune Responses to Pneumococcal Conjugate Vaccine in HIV-Infected and HIV-Uninfected Children 5 Years after Vaccination

BACKGROUND Administration of pneumococcal conjugate vaccine (PCV) to HIV-infected children during infancy confers limited long-term protection in the absence of antiretroviral therapy. The objective of the present study was to determine the immune responses to PCV at 5 years of age in HIV-infected and HIV-uninfected children who had been primed with vaccine during infancy (i.e., previous vaccinees) and in those receiving their first dose of vaccine (i.e., control subjects). METHODS Serotype-specific antibodies were quantified by enzyme immunoassay, and antibody functionality to serotypes 6B, 9V, and 19F were evaluated using an opsonophagocytic killing assay 1 month after vaccination. RESULTS Of the HIV-infected children, 19.7% were receiving antiretroviral therapy, and 40.5% had a CD4(+) cell percentage <15%. Geometric mean concentrations of antibody and the proportion with a concentration 0.35 microg/mL after vaccination were greater among HIV-uninfected children than among HIV-infected children for both previous vaccinees and control subjects. Antibody concentrations after vaccination were lower for 3 of 7 serotypes among HIV-infected previous vaccinees than among control subjects. Detectable opsonophagocytic activity to all studied serotypes was lower among HIV-infected than among HIV-uninfected previous vaccinees and control subjects. Postvaccination antibody-mediated killing activity as determined by the opsonophagocytic killing assay was enhanced in control subjects compared with previous vaccinees among HIV-uninfected children. CONCLUSION HIV-infected vaccinees experience a partial loss of anamnestic responses to PCV. The optimal timing and frequency of booster vaccination as well as the responses to them among HIV-infected children need to be determined.