Dynamic molecular changes during the first week of human life follow a robust developmental trajectory.

Systems biology can unravel complex biology but has not been extensively applied to human newborns, a group highly vulnerable to a wide range of diseases. We optimized methods to extract transcriptomic, proteomic, metabolomic, cytokine/chemokine, and single cell immune phenotyping data from <1 ml of blood, a volume readily obtained from newborns. Indexing to baseline and applying innovative integrative computational methods reveals dramatic changes along a remarkably stable developmental trajectory over the first week of life. This is most evident in changes of interferon and complement pathways, as well as neutrophil-associated signaling. Validated across two independent cohorts of newborns from West Africa and Australasia, a robust and common trajectory emerges, suggesting a purposeful rather than random developmental path. Systems biology and innovative data integration can provide fresh insights into the molecular ontogeny of the first week of life, a dynamic developmental phase that is key for health and disease.

Pneumococcal responses are similar in Papua New Guinean children aged 3-5 years vaccinated in infancy with pneumococcal polysaccharide vaccine with or without prior pneumococcal conjugate vaccine, or without pneumococcal vaccination.

TRIAL DESIGN: In an earlier trial, Papua New Guinean (PNG) children at high risk of pneumococcal disease were randomized to receive 0 or 3 doses of 7-valent pneumococcal conjugate vaccine (PCV7), followed by a single dose of 23-valent pneumococcal polysaccharide vaccine (PPV23) at 9 months of age. We here studied in a non-randomized follow-up trial the persistence of pneumococcal immunity in these children at 3-5 years of age (n = 132), and in 121 community controls of a similar age with no prior pneumococcal vaccination. METHODS: Circulating IgG antibody titers to all PCV7 and PPV23-only serotypes 2, 5 and 7F were measured before and after challenge with 1/5th of a normal PPV23 dose. Serotype-specific memory B-cells were enumerated at 10 months and 3-5 years of age for a subgroup of study children. RESULTS: Serotype-specific IgG antibody titers before and after challenge were similar for children who received PCV7/PPV23, PPV23 only, or no pneumococcal vaccines. Before challenge, at least 89% and 59% of children in all groups had serotype-specific titers ≥ 0.35µg/ml and ≥ 1.0 µg/ml, respectively. Post-challenge antibody titers were higher or similar to pre-challenge titers for most children independent of pneumococcal vaccination history. The rise in antibody titers was significantly lower when pre-challenge titers were higher. Overall the relative number of serotype-specific memory B-cells remained the same or increased between 10 months and 3-5 years of age, and there were no differences in serotype-specific memory B-cell numbers at 3-5 years of age between the three groups. CONCLUSIONS: Immunity induced by PCV7 and/or PPV23 immunization in infancy does not exceed that of naturally acquired immunity in 3-5-year-old children living in a highly endemic area. Also, there was no evidence that PPV23 immunization in the first year of life following PCV7 priming induces longer-term hypo-responsiveness. TRIAL REGISTRATION: Clinicaltrials.gov NCT01414504 and NCT00219401.

Rationale and methods of a randomized controlled trial of immunogenicity, safety and impact on carriage of pneumococcal conjugate and polysaccharide vaccines in infants in Papua New Guinea.

BACKGROUND: Children in third-world settings including Papua New Guinea (PNG) experience early onset of carriage with a broad range of pneumococcal serotypes, resulting in a high incidence of severe pneumococcal disease and deaths in the first 2 years of life. Vaccination trials in high endemicity settings are needed to provide evidence and guidance on optimal strategies to protect children in these settings against pneumococcal infections. METHODS: This report describes the rationale, objectives, methods, study population, follow-up and specimen collection for a vaccination trial conducted in an endemic and logistically challenging setting in PNG. The trial aimed to determine whether currently available pneumococcal conjugate vaccines (PCV) are suitable for use under PNG's accelerated immunization schedule, and that a schedule including pneumococcal polysaccharide vaccine (PPV) in later infancy is safe and immunogenic in this high-risk population. RESULTS: This open randomized-controlled trial was conducted between November 2011 and March 2016, enrolling 262 children aged 1 month between November 2011 and April 2014. The participants were randomly allocated (1:1) to receive 10-valent PCV (10vPCV) or 13-valent PCV (13vPCV) in a 1-2-3-month schedule, with further randomization to receive PPV or no PPV at age 9 months, followed by a 1/5th PPV challenge at age 23 months. A total of 1229 blood samples were collected to measure humoral and cellular immune responses and 1238 nasopharyngeal swabs to assess upper respiratory tract colonization and carriage load. Serious adverse events were monitored throughout the study. Of the 262 children enrolled, 87% received 3 doses of PCV, 79% were randomized to receive PPV or no PPV at age 9 months, and 67% completed the study at 24 months of age with appropriate immunization and challenge. CONCLUSION: Laboratory testing of the many samples collected during this trial will determine the impact of the different vaccine schedules and formulations on nasopharyngeal carriage, antibody production and function, and immune memory. The final data will inform policy on pneumococcal vaccine schedules in countries with children at high risk of pneumococcal disease by providing direct comparison of an accelerated schedule of 10vPCV and 13vPCV and the potential advantages of PPV following PCV immunization. TRIAL REGISTRATION: ClinicalTrials.gov CTN NCT01619462, retrospectively registered on May 28, 2012.

Limited impact of neonatal or early infant schedules of 7-valent pneumococcal conjugate vaccination on nasopharyngeal carriage of Streptococcus pneumoniae in Papua New Guinean children: A randomized controlled trial.

Streptococcus pneumoniae is a leading cause of pneumonia, the most common cause of childhood death. Papua New Guinean children experience high rates of nasopharyngeal pneumococcal colonization within weeks of birth, predisposing them to pneumococcal disease. In a trial to determine the safety and immunogenicity of early infant vaccination with 7-valent pneumococcal conjugate vaccine (7vPCV), we investigated the impact of early schedules on pneumococcal carriage. Infants were randomized at birth to receive 7vPCV in a 0-1-2-month (n = 101) or a 1-2-3-month (n = 105) schedule or no 7vPCV (n = 106). All children received 23-valent pneumococcal polysaccharide vaccine at age 9 months. We cultured nasopharyngeal swabs (NPS) collected at ages 1, 2, 3, 4 weeks and 3, 9, 18 months, and middle ear discharge if present. Pneumococcal serotypes were identified by the Quellung reaction. A total of 1761 NPS were cultured. The prevalence of pneumococcal carriage was 22% at 1 week of age, rising to 80% by age 3 months and remained >70% thereafter, with high-density carriage in 42% of pneumococcus-positive samples. We identified 63 different serotypes; 43% of isolates from controls were 13vPCV serotypes. There were no significant differences in 7vPCV serotype carriage between 7vPCV recipients and controls at any age (22% vs. 31% at 9 months, p = 0.2). At age 9 months the prevalence of non-7vPCV carriage was 17% higher in 7vPCV recipients (48%) than in controls (25%, p = 0.02). More non-7vPCV serotypes were isolated from ear discharge in 16 7vPCV recipients than from 4 controls (48% vs. 25%, p = 0.13). The limited impact of neonatal or accelerated infant 7vPCV schedules on vaccine serotype carriage is probably due to the early onset of dense carriage of a broad range of pneumococcal serotypes. While serotype-independent pneumococcal vaccines are needed in high-risk populations, the underlying environmental factors and sources of infection must be investigated. http://clinicaltrials.gov/ct2/show/NCT00219401.

The epidemiology of malaria in the Papua New Guinea highlands: 6. Simbai and Bundi, Madang Province.

Although predominantly a lowland province, Madang also includes highland areas such as Simbai and Bundi along the northern highland fringe. While the malaria situation in the coastal lowlands has been studied in great detail, the current malaria situation in the highland fringe communities has not been studied in depth since the 1960s. A series of recent malariological surveys found that the malaria situation has changed little over the last 40 years in both Simbai and Bundi. In the Simbai area there is little malaria transmission in villages above 1400 m, with a prevalence rate (PR) of 2.5-4.2%. Below 1400 m, however, there is moderate to high transmission (PR 8.6-24.7%) with surprisingly little difference in prevalence rates between survey villages, despite large differences in altitude. Prevalence rates of malaria infection were low in all Bundi villages (2.5-8.5%) with most infections occurring in adolescents and adults, which indicates limited acquisition of effective immunity to malaria and the possibility that many infections are acquired when travelling to the highly malarious lowlands area. Based on spleen rates the lower Simbai area would be regarded as mesoendemic, and the upper Simbai and Bundi areas as hypoendemic. Only in the lower Simbai area is malaria a major cause of febrile illness. However, in all areas village mean haemoglobin (Hb) levels were highly correlated with the prevalence of malaria infections, while concurrent parasitaemia reduced individual Hb levels by 1.3 g/dl (CI95 [1.0-1.5], p < 0.001) and significantly increased the risk for moderate-to-severe anaemia (Hb < 8 g/dl) (adjusted odds ratio 5.6, CI95 [3.6-8.6], p < 0.001). Based on the survey results, areas of different malaria epidemiology are delineated and options for control in each area are discussed.

The epidemiology of malaria in the Papua New Guinea highlands: 3. Simbu Province.

Two very distinct malaria zones can be found within Simbu Province. The north of the province is characterized by the absence or very low level of local malaria transmission, but there is a considerable risk of epidemics prevalent in the lower-lying parts. During non-epidemic periods, parasite prevalence was usually under 5%, with similar frequencies for Plasmodium falciparum and P. vivax (47% each), and malaria was an only minor source of febrile illness. During epidemics, however, 13-36% of people were infected, predominantly with P. falciparum (64%), and high levels of severe morbidity were present. In south Simbu malaria is clearly endemic with an overall prevalence of 35%, combined with a strong age-dependence of infections, low haemoglobin levels, high rates of enlarged spleen and moderate to severe anaemia (haemoglobin level < 7.5 g/dl) in children. The malaria epidemiology in south Simbu is thus more similar to the lowlands than to other highlands areas. Epidemic prevention, surveillance and response in the north, and bednet distribution and strengthening of curative services in the south, are therefore the priorities for malaria control in Simbu Province.