Contradictory mortality results in early 2-dose measles vaccine trials: interactions with oral polio vaccine may explain differences.

Objectives: Between 2003 and 2019, three trials (randomised controlled trials [RCTs]) in Guinea-Bissau randomised infants to an early 2-dose measles vaccine (MV) schedule at 4 and 9 months vs standard MV at 9 months. The RCTs produced contradictory mortality results; the effect being beneficial in the 2-dose group in the first but tending to have higher mortality in the last two RCTs. We hypothesised that increased frequency of campaigns with oral polio vaccine (C-OPV) explained the pattern.

Effect of early two-dose measles vaccination on childhood mortality and modification by maternal measles antibody in Guinea-Bissau, West Africa: A single-centre open-label randomised controlled trial.

Background: Early 2-dose measles vaccine (MV) at 4 and 9 months of age vs. the WHO strategy of MV at 9 months of age reduced all-cause child mortality in a previous trial. We aimed to test two hypotheses: 1) a 2-dose strategy reduces child mortality between 4 and 60 months of age by 30%; 2) receiving early MV at 4 months in the presence versus absence of maternal measles antibodies (MatAb) reduces child mortality by 35%.

Sex-Differential Impact of Human Cytomegalovirus Infection on In Vitro Reactivity to Toll-Like Receptor 2, 4 and 7/8 Stimulation in Gambian Infants.

Human cytomegalovirus (HCMV) infection rates approach 100% by the first year of life in low-income countries. It is not known if this drives changes to innate immunity in early life and thereby altered immune reactivity to infections and vaccines. Given the panoply of sex differences in immunity, it is feasible that any immunological effects of HCMV would differ in males and females.

Limited Impact of Human Cytomegalovirus Infection in African Infants on Vaccine-Specific Responses Following Diphtheria-Tetanus-Pertussis and Measles Vaccination.

Human cytomegalovirus (HCMV) infection has a profound effect on the human immune system, causing massive clonal expansion of CD8, and to a lesser extend CD4 T cells. The few human trials that have explored the effect of HCMV infection on responses to vaccination are conflicting, with some studies suggesting no effect whilst others suggest decreased or increased immune responses. Recent studies indicate substantial differences in overall immune system reactivity to vaccines based on age and sex, particularly cellular immunity.

Measles Vaccination in Presence of Measles Antibody May Enhance Child Survival.

In trials of early two-dose measles vaccination (MV), with the first dose being given before 9 months of age, vaccination in the presence of maternal antibody reduced mortality 2- to 3-fold compared with MV in the presence of no measles antibody. We tested this finding in two historical studies in which the children had received one dose of MV. We used data from a surveillance study of seroconversion after standard-titer MV (Schwarz strain) (Study 1) and a trial of early medium-titer MV (Edmonston-Zagreb strain) in which a pre-vaccination blood sample had been collected (Study 2).

A Two-Center Randomized Trial of an Additional Early Dose of Measles Vaccine: Effects on Mortality and Measles Antibody Levels.

Background: In addition to protecting against measles, measles vaccine (MV) may have beneficial nonspecific effects. We tested the effect of an additional early MV on mortality and measles antibody levels.

Methods: Children aged 4-7 months at rural health and demographic surveillance sites in Burkina Faso and Guinea-Bissau were randomized 1:1 to an extra early standard dose of MV (Edmonston-Zagreb strain) or no extra MV 4 weeks after the third diphtheria-tetanus-pertussis-hepatitis B-Haemophilus influenzae type b vaccine.

KIR content genotypes associate with carriage of hepatitis B surface antigen, e antigen and HBV viral load in Gambians.

Background: Hepatocellular carcinoma (HCC) causes over 800,000 deaths worldwide annually, mainly in low income countries, and incidence is rising rapidly in the developed world with the spread of hepatitis B (HBV) and C (HCV) viruses. Natural Killer (NK) cells protect against viral infections and tumours by killing abnormal cells recognised by Killer-cell Immunoglobulin-like Receptors (KIR). Thus genes and haplotypes encoding these receptors may be important in determining both outcome of initial hepatitis infection and subsequent chronic liver disease and tumour formation.

Negative Correlation between Circulating CD4FOXP3CD127 Regulatory T Cells and Subsequent Antibody Responses to Infant Measles Vaccine but Not Diphtheria-Tetanus-Pertussis Vaccine Implies a Regulatory Role.

Regulatory T cells (Tregs) play a key homeostatic role by suppressing immune responses. They have been targeted in mouse and human cancer studies to improve vaccine immunogenicity and tumor clearance. A number of commercially available drugs and experimental vaccine adjuvants have been shown to target Tregs.

Does oral polio vaccine have non-specific effects on all-cause mortality? Natural experiments within a randomised controlled trial of early measles vaccine.

Background: BCG and measles vaccine (MV) may have beneficial non-specific effects (NSEs). If an unplanned intervention with a vaccine (a natural experiment) modifies the estimated effect in a randomised controlled trial (RCT), this suggests NSEs. We used this approach to test NSEs of triple oral polio vaccine (OPV).

Randomized Trials Comparing Inactivated Vaccine After Medium- or High-titer Measles Vaccine With Standard Titer Measles Vaccine After Inactivated Vaccine: A Meta-analysis.

Background: Observational studies have suggested that girls have higher mortality if their most recent immunization is an inactivated vaccine rather than a live vaccine. We therefore reanalyzed 5 randomized trials of early measles vaccine (MV) in which it was possible to compare an inactivated vaccines [after medium-titer MV (MTMV) or high-titer MV (HTMV)] and a live standard titer MV (after an initial inactivated vaccine).

Methods: The trials were conducted in Sudan, Senegal, The Gambia and Guinea-Bissau.

Revaccination with Live Attenuated Vaccines Confer Additional Beneficial Nonspecific Effects on Overall Survival: A Review.

Background: Live vaccines against measles (MV), tuberculosis (BCG), polio (OPV) and smallpox reduce mortality more than explained by target-disease prevention. The beneficial nonspecific effects (NSEs) of MV are strongest when MV is given in presence of maternal antibodies. We therefore hypothesised that revaccination in presence of prior immunity enhances beneficial NSEs.

The presence of prolines in the flanking region of an immunodominant HIV-2 gag epitope influences the quality and quantity of the epitope generated.

Both the recognition of HIV-infected cells and the immunogenicity of candidate CTL vaccines depend on the presentation of a peptide epitope at the cell surface, which in turn depends on intracellular antigen processing. Differential antigen processing maybe responsible for the differences in both the quality and the quantity of epitopes produced, influencing the immunodominance hierarchy of viral epitopes. Previously, we showed that the magnitude of the HIV-2 gag-specific T-cell response is inversely correlated with plasma viral load, particularly when responses are directed against an epitope, 165 DRFYKSLRA173 , within the highly conserved Major Homology Region of gag-p26.

Early virological and immunological events in asymptomatic Epstein-Barr virus infection in African children.

Epstein-Barr virus (EBV) infection often occurs in early childhood and is asymptomatic. However, if delayed until adolescence, primary infection may manifest as acute infectious mononucleosis (AIM), a febrile illness characterised by global CD8+ T-cell lymphocytosis, much of it reflecting a huge expansion of activated EBV-specific CD8+ T-cells. While the events of AIM have been intensely studied, little is known about how these relate to asymptomatic primary infection.

Is early measles vaccination better than later measles vaccination?

WHO recommends delaying measles vaccination (MV) until maternal antibody has waned. However, early MV may improve child survival by reducing mortality from conditions other than measles infection. We tested whether early MV improves child survival compared with later MV.

Measles vaccination in the presence or absence of maternal measles antibody: impact on child survival.

Background: Measles vaccine (MV) has a greater effect on child survival when administered in early infancy, when maternal antibody may still be present.

Methods: To test whether MV has a greater effect on overall survival if given in the presence of maternal measles antibody, we reanalyzed data from 2 previously published randomized trials of a 2-dose schedule with MV given at 4-6 months and at 9 months of age. In both trials antibody levels had been measured before early measles vaccination.

Efficacy and effectiveness of infant vaccination against chronic hepatitis B in the Gambia Hepatitis Intervention Study (1986-90) and in the nationwide immunisation program.

Background: Gambian infants were not routinely vaccinated against hepatitis B virus (HBV) before 1986. During 1986-90 the Gambia Hepatitis Intervention Study (GHIS) allocated 125,000 infants, by area, to vaccination or not and thereafter all infants were offered the vaccine through the nationwide immunisation programme. We report HBV serology from samples of GHIS vaccinees and unvaccinated controls, and from children born later.

Mortality rates in people dually infected with HIV-1/2 and those infected with either HIV-1 or HIV-2: a systematic review and meta-analysis.

Objective: As compared to HIV-1 infection, HIV-2 is less transmissible, disease progression is slower, and the mortality risk is lower. It has been suggested that HIV-2 infection inhibits the progression of HIV-1 in individuals dually infected by HIV-1 and HIV-2 (HIV-D). We examined whether the mortality rates in dually infected individuals differ from those in persons infected with either HIV-1 or HIV-2.

Host iron redistribution as a risk factor for incident tuberculosis in HIV infection: an 11-year retrospective cohort study.

Background: Identifying people at higher risk of developing tuberculosis with human immunodeficiency virus (HIV) infection may improve clinical management of co-infections. Iron influences tuberculosis (TB) pathogenesis, but understanding the exact mechanisms of how and timing of when iron is involved remains challenging since biological samples are rarely available from the disease susceptibility period due to the difficulty in predicting in who and when, if ever, TB will develop. The objective of this research was to determine how host iron status measured at HIV diagnosis and genotypes related to host iron metabolism were associated with incident TB.

Clinical predictors cannot replace biological predictors in HIV-2 infection in a community setting in West Africa.

Objective: To identify clinical predictors of mortality in HIV-2-infected individuals that may be used in place of CD4 count or plasma viral load (PVL) to guide treatment management in resource-limited settings.

Methods: A prospective community cohort study of HIV-infected and HIV-negative individuals in a rural area of Guinea-Bissau has been ongoing since 1989. In 2003 participants were invited for a clinical examination and blood tests.

Non-specific effects of standard measles vaccine at 4.5 and 9 months of age on childhood mortality: randomised controlled trial.

Objective: To examine in a randomised trial whether a 25% difference in mortality exists between 4.5 months and 3 years of age for children given two standard doses of Edmonston-Zagreb measles vaccines at 4.5 and 9 months of age compared with those given one dose of measles vaccine at 9 months of age (current policy).

CD4 intragenic SNPs associate with HIV-2 plasma viral load and CD4 count in a community-based study from Guinea-Bissau, West Africa.

Objectives: The human genetics of HIV-2 infection and disease progression is understudied. Therefore, we studied the effect of variation in 2 genes that encode products critical to HIV pathogenesis and disease progression: CD4 and CD209.

Design: This cross-sectional study consisted of 143 HIV-2, 30 HIV-1 + HIV-2 and 29 HIV-1-infected subjects and 194 uninfected controls recruited from rural Guinea-Bissau.

Host genetic factors and vaccine-induced immunity to HBV infection: haplotype analysis.

Hepatitis B virus (HBV) infection remains a significant health burden world-wide, although vaccines help decrease this problem. We previously identified associations of single nucleotide polymorphisms in several candidate genes with vaccine-induced peak antibody level (anti-HBs), which is predictive of long-term vaccine efficacy and protection against infection and persistent carriage; here we report on a haplotype-based analysis. A total of 688 SNPs from 117 genes were examined for a two, three and four sliding window haplotype analysis in a Gambian cohort.

Influence of HLA class I and HLA-KIR compound genotypes on HIV-2 infection and markers of disease progression in a Manjako community in West Africa.

Overall, the time to AIDS after HIV-2 infection is longer than with HIV-1, and many individuals infected with HIV-2 virus remain healthy throughout their lives. Multiple HLA and KIR gene products have been implicated in the control of HIV-1, but the effect of variation at these loci on HIV-2 disease is unknown. We show here for the first time that HLA-B*1503 is associated significantly with poor prognosis after HIV-2 infection and that HLA-B*0801 is associated with susceptibility to infection.