Marta C. Nunes

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 antiretroviral treatment on the burden of invasive pneumococcal disease in South African children: a time series analysis

Objective:HIV infection is a major risk factor for invasive pneumococcal disease (IPD). A national antiretroviral program was initiated in South Africa in 2004. This study evaluates the impact of the highly active antiretroviral therapy (HAART) treatment program on the burden of IPD among African children. Design:Retrospective analysis of laboratory-confirmed IPD among children under 18 years of age, from 2003 to 2008. Methods:The periods 2003–2004, 2005–2006 and 2007–2008 were defined as the early, intermediate and established HAART eras, respectively. Pneumococcal conjugate vaccine was not introduced into public immunization during this period. Results:One thousand, one hundred and seventy-one episodes of IPD were identified over the study period. Among HIV-infected children under 18 years, the burden of IPD decreased by 50.8% [95% confidence interval (CI) 41.5–58.7] and the incidence of IPD-related mortality declined by 65.2% (95% CI 47.2–77.0) from the early compared to the established HAART era. This decline in HIV-infected children was evident for pneumococcal bacteremia and pneumococcal meningitis. In addition, similar reductions were observed for serotypes included in a 7-valent pneumococcal conjugate vaccine and nonvaccine serotypes. The burden of IPD remained unchanged in HIV-uninfected children under 18 years of age over these periods. The risk of IPD, however, remained 42-fold greater in HIV-infected compared to HIV-uninfected children in the established HAART era. Conclusions:Although the HAART program has been associated with significant declines in IPD morbidity and mortality, HIV-infected African children with access to HAART remain a high-risk group for IPD. These children should therefore be prioritized in the prevention of IPD.

Safety, immunogenicity and efficacy of pneumococcal conjugate vaccine in HIV-infected individuals

Streptococcus pneumoniae is the leading bacterial opportunistic infection in HIV-infected individuals. Anti-retroviral treatment (ART) of HIV-infected individuals reduces their risk of invasive pneumococcal disease (IPD), however, it remains 20- to 40-fold greater compared with age-matched general population. This review summarizes the available published data on the immunogenicity, safety and efficacy of pneumococcal polysaccharide-protein conjugate vaccines (PCV) in HIV-infected children and adults. Several studies have demonstrated that PCV are safe in the HIV-infected persons. Although PCV are immunogenic in HIV-infected infants, the antibodies produced are functionally impaired, there is possibly a lack or loss of anamnestic responses and immunity declines in later life However, quantitative and qualitative antibody responses to PCV in HIV-infected infants are enhanced when vaccination occurs whilst on ART, as well as if vaccination occurs when the CD4+ cell percentage is ≥ 25% and if the nadir CD4+ is >15%. Although the efficacy of PCV was lower, the vaccine preventable burden of hospitalization for IPD and clinical pneumonia were 18-fold and 9-fold greater, respectively, in HIV-infected children compared with –uninfected children. In HIV-infected adults, PCV vaccination induces more durable and functional antibody responses in individuals on ART at the time of vaccination than in ART-naive adults, independently of baseline CD4+ cell count, although there does not appear to be much benefit from a second-dose of PCV. PCV has also been shown to reduce the risk of recurrent IPD by 74% in HIV-infected adults not on ART, albeit, also with subsequent decline in immunity and protection.

Persistent high burden of invasive pneumococcal disease in South African HIV-infected adults in the era of an antiretroviral treatment program.

Background Highly active antiretroviral treatment (HAART) programs have been associated with declines in the burden of invasive pneumococcal disease (IPD) in industrialized countries. The aim of this study was to evaluate trends in IPD hospitalizations in HIV-infected adults in Soweto, South Africa, associated with up-scaling of the HAART program from 2003 to 2008. Methods Laboratory-confirmed IPD cases were identified from 2003 through 2008 through an existing surveillance program. The period 2003-04 was designated as the early-HAART era, 2005–06 as the intermediate-HAART era and 2007–08 as the established-HAART era. The incidence of IPD was compared between the early-HAART and established-HAART eras in HIV-infected and–uninfected individuals. Results A total of 2,567 IPD cases among individuals older than 18 years were reported from 2003 through 2008. Overall incidence of IPD (per 100,000) did not change during the study period in HIV-infected adults (207.4 cases in the early-HAART and 214.0 cases in the established-HAART era; p = 0.55). IPD incidence, actually increased 1.16-fold (95% CI: 1.01; 1.62) in HIV-infected females between the early-and established-HAART eras (212.1 cases and 246.2 cases, respectively; p = 0.03). The incidence of IPD remained unchanged in HIV-uninfected adults across the three time periods. Conclusion Despite a stable prevalence of HIV and the increased roll-out of HAART for treatment of AIDS patients in our setting, the burden of IPD has not decreased among HIV-infected adults. The study indicates a need for ongoing monitoring of disease and HAART program effectiveness to reduce opportunistic infections in African adults with HIV/AIDS, as well as the need to consider alternate strategies including pneumococcal conjugate vaccine immunization for the prevention of IPD in HIV-infected adults.

Review on the immunogenicity and safety of PCV‑13 in infants and toddlers

Pneumococcal polysaccharide–protein conjugate vaccines (PCVs) generally protect against vaccine-serotype-specific pneumococcal disease. Additional serotypes included in the new 13-valent PCV (PCV-13) formulation and not in the first-generation 7-valent PCV (PCV-7) formulations are 1, 3, 5, 6A, 7F and 19A. Importantly, serotype 1 is associated with a high proportion and burden of pneumococcal disease in low-income countries, whilst serotype 19A emerged as the dominant disease-causing serotype following widespread PCV-7 immunization in the USA. In this article we present the available data on the immunogenicity and safety of PCV-13 in infants and children. Noninferiority studies indicate a similar immunogenicity profile between PCV-13 and PCV-7 recipients against most of the common serotypes. A favorable immunogenicity profile was also observed for at least five of the additional serotypes in PCV-13. An attenuated anamnestic response to serotype 3 was reported in five out of 14 studies. PCV-13 was demonstrated to have a similar acceptable safety profile to PCV-7 and no interference in immunogenicity of other concomitantly administered childhood vaccines was observed among PCV-13 recipients.

Duration of Infant Protection Against Influenza Illness Conferred by Maternal Immunization: Secondary Analysis of a Randomized Clinical Trial.

IMPORTANCE Influenza immunization of women during pregnancy protects the young infants against influenza illness. The duration of this protection remains unclear. OBJECTIVE To evaluate the duration of infant protection conferred by maternal immunization and its association with transplacental antibody transfer. DESIGN, SETTING, AND PARTICIPANTS Infants born to women who participated in a randomized, double-blind, placebo-controlled clinical trial in 2011 and 2012 on the safety, immunogenicity, and efficacy of trivalent inactivated influenza vaccine (IIV3) during pregnancy were followed up during the first 6 months of life for polymerase chain reaction (PCR)-confirmed influenza illness. In a secondary analysis of a subset of infants, hemagglutination inhibition (HAI) antibodies were measured. The study was performed at a single center in South Africa. The secondary analysis was performed in October 2014. EXPOSURE Maternal immunization for influenza. MAIN OUTCOMES AND MEASURES The vaccines efficacy against PCR-confirmed influenza illness and the percentage of infants with HAI titers of 1:40 or more by age group. RESULTS There were 1026 infants (47.2% female) born to IIV3 recipients and 1023 infants (47.3% female) born to placebo recipients who were included in the analysis of the vaccines efficacy. The vaccines efficacy against PCR-confirmed influenza illness was highest among infants 8 weeks of age or younger at 85.6% (95% CI, 38.3%-98.4%) and decreased with increasing age to 25.5% (95% CI, -67.9% to 67.8%) among infants 8 to 16 weeks of age and to 30.3% (95% CI, -154.9% to 82.6%) among infants 16 to 24 weeks of age. Similarly, in the IIV3 group, the percentage of infants with HAI titers of 1:40 or more to the influenza vaccine strains decreased from more than 56% in the first week of life to less than 40% at 16 weeks of age and less than 10.0% at 24 weeks of age. CONCLUSIONS AND RELEVANCE Maternal immunization conferred protection against infection in the infants for a limited period during early life. The lack of protection beyond 8 weeks of age correlated with a decrease in maternally derived antibodies. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01306669.

Kinetics of Hemagglutination-Inhibiting Antibodies Following Maternal Influenza Vaccination Among Mothers With and Those Without HIV Infection and Their Infants

BACKGROUND We evaluated the immunogenicity of trivalent inactivated influenza vaccine (IIV3) in pregnant women with and those without human immunodeficiency virus (HIV) infection and the persistence of hemagglutination-inhibiting antibodies in mothers and infants. METHODS Antibodies were measured before vaccination, 1 month after vaccination, at delivery, and at postpartum week 24 in mothers and within 1 week of birth and at 8, 16, and 24 weeks of age in infants. RESULTS We enrolled 98 HIV-uninfected and 100 HIV-infected pregnant women, including 93% with a CD4(+) T-cell count of ≥ 200 cells/µL. Compared with HIV-uninfected women, HIV-infected women had lower seroconversion rates (ranging from 63%-92% vs 36%-40%), lower antibody titers through postpartum week 24, and overlapping antibody half-lives (ranging from 106-121 vs 87-153 days). Infant titers were lower than the maternal titers within 1 week of delivery, regardless of vaccine strain and HIV exposure status. Compared with HIV-unexposed infants, HIV-exposed infants had a similar transplacental influenza virus antibody transfer ratio, lower titers, and a lower frequency of titers ≥ 1:40 (ranging from 82%-95% vs 43%-79%) at birth and higher antibody half-lives (ranging from 43-45 vs 56-65 days). CONCLUSIONS Compared with HIV-uninfected pregnant women, HIV-infected pregnant women had lower antibody responses and persistence. Compared with HIV-unexposed infants, HIV-exposed infants had lower antibody levels at birth but similar antibody levels after 8 weeks of life. Early IIV3 administration during pregnancy did not decrease antibody titers among infants at birth.

How host heterogeneity governs tuberculosis reinfection

Recurrent episodes of tuberculosis (TB) can be due to relapse of latent infection or exogenous reinfection, and discrimination is crucial for control planning. Molecular genotyping of Mycobacterium tuberculosis isolates offers concrete opportunities to measure the relative contribution of reinfection in recurrent disease. Here, a mathematical model of TB transmission is fitted to data from 14 molecular epidemiology studies, enabling the estimation of relevant epidemiological parameters. Meta-analysis reveals that rates of reinfection after successful treatment are higher than rates of new TB, raising an important question about the underlying mechanism. We formulate two alternative mechanisms within our model framework: (i) infection increases susceptibility to reinfection or (ii) infection affects individuals differentially, thereby recruiting high-risk individuals to the group at risk for reinfection. The second mechanism is better supported by the fittings to the data, suggesting that reinfection rates are inflated through a population phenomenon that occurs in the presence of heterogeneity in individual risk of infection. As a result, rates of reinfection are higher when measured at the population level even though they might be lower at the individual level. Finally, differential host recruitment is modulated by transmission intensity, being less pronounced when incidence is high.

Temporal changes in pneumococcal colonization in a rural African community with high HIV prevalence following routine infant pneumococcal immunization.

Background: Pneumococcal conjugate vaccine (PCV) immunization of children decreases their risk of nasopharyngeal acquisition of vaccine serotypes. We studied the impact of routine infant PCV immunization alone on the epidemiology of nasopharyngeal pneumococcal colonization among a rural African community with high prevalence of HIV positivity. Methods: Two cross-sectional surveys were undertaken in a rural South African community from May to October 2009 (period 1) and 2011 (period 2). Seven-valent PCV was introduced into the public immunization program for infants in April 2009, without catch-up campaign for older children. Randomly selected households with at least 1 child <2 years of age were recruited. Nasopharyngeal swabs from all consenting household members were obtained for Streptococcus pneumoniae culture and serotyping by Quellung method. Results: The median ages (SD) of children enrolled were 4.32 (SD, 3.4) and 3.80 (SD, 3.4) years in periods 1 and 2, respectively. Overall, the prevalence of vaccine serotype colonization declined from 18.3% (368/2010) in period 1 to 11.4% (418/3659) by period 2 (P < 0.0001). This included reductions (adjusted risk ratio) of 50% [95% confidence interval (95% CI): 0.42–0.59], 34% (95% CI: 0.48–0.92) and 64% (95% CI: 0.18–0.74) in age groups <2 years, 6–12 years and adults. The prevalence of vaccine serotype colonization among primary caregivers decreased from 10.2% to 5.4% (P ⩽ 0.001) by period 2. The prevalence of nonvaccine serotype colonization increased by 35% (95% CI: 1.17–1.56) among <2-year-old children by period 2, while it declined by 45–54% among adolescents and adults. Conclusions: An indirect effect of PCV7 was realized in a high HIV prevalence setting within 2 years of PCV introduction. The unexpected decline in nonvaccine serotypes colonization among adolescents/adults may indicate lag in replacement colonization by nonvaccine serotypes in this group.

Interrelationship of Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus colonization within and between pneumococcal-vaccine naïve mother-child dyads

BackgroundA high prevalence of bacterial nasopharyngeal co-infections has been reported in children, however, such data is limited in adults. We examined the interaction of Haemophilus influenzae, Staphylococcus aureus and Streptococcus pneumoniae pharyngeal colonization in mother-child dyads.MethodsPneumococcal-vaccine naïve children and their mothers had pharyngeal swabs undertaken at 1.6, 2.5, 3.5, 4.5, 7.4, 9.5, 12.5, 16.2 and 24.2 months of child’s age. Swabs were cultured for S. pneumoniae, H. influenzae and S. aureus using standard microbiologic methods. Multivariate generalized estimating equation-models were used to explore the associations of the three bacteria within and between children and their mothers.ResultsIn children, the observed probability of co-colonization was higher than expected. Well-defined associations in colonization between the bacteria were observed in children but not among mothers. In children, a synergistic association was observed between S. pneumoniae and H. influenzae (Adjusted odds ratio (AOR): 1.75, 95% CI: 1.32-2.32) and a negative association between S. pneumoniae and S. aureus (AOR: 0.51, 95% CI: 0.39-0.67) or H. influenzae and S. aureus (AOR: 0.24, 95% CI: 0.16-0.34) colonization. Additionally, all three bacteria had a higher likelihood of concurrent colonization. There was a strong association in colonization by the bacteria in children and their mothers, including increased likelihood of maternal colonization if the child was colonized by S. pneumoniae (AOR: 1.84, 95% CI: 1.28-2.63) and H. influenzae (AOR: 6.34, 95% CI: 2.24-18.0).ConclusionsThe effects of immunization of children with pneumococcal-conjugate-vaccine in settings such as ours needs monitoring with regard to potential changes of pharyngeal bacterial ecology which could occur in vaccinated and –unvaccinated age-groups.