Highlights • Pneumococcal protein antigens could provide serotype-independent protection. • Two PHiD-CV/dPly/PhtD vaccine formulations were assessed in healthy infants. • Both protein-based vaccines ...elicited immune responses to pneumococcal proteins. • The vaccines had no impact on pneumococcal nasopharyngeal carriage prevalence. • Future evaluations will assess their impact against pneumococcal disease endpoints.
Other than clean drinking water, vaccines have been the most effective public health intervention in human history, yet their full potential is still untapped. To date, vaccine development has been ...largely limited to empirical approaches focused on infectious diseases and has targeted entire populations, potentially disregarding distinct immunity in vulnerable populations such as infants, elders, and the immunocompromised. Over the past few decades innovations in genetic engineering, adjuvant discovery, formulation science, and systems biology have fueled rapid advances in vaccine research poised to consider demographic factors (
, age, sex, genetics, and epigenetics) in vaccine discovery and development. Current efforts are focused on leveraging novel approaches to vaccine discovery and development to optimize vaccinal antigen and, as needed, adjuvant systems to enhance vaccine immunogenicity while maintaining safety. These approaches are ushering in an era of precision vaccinology aimed at tailoring immunization for vulnerable populations with distinct immunity. To foster collaboration among leading vaccinologists, government, policy makers, industry partners, and funders from around the world, the
at Boston Children's Hospital hosted the 2
International Precision Vaccines Conference (IPVC) at Harvard Medical School on the 17
-18
October 2019. The conference convened experts in vaccinology, including vaccine formulation and adjuvantation, immunology, cell signaling, systems biology, biostatistics, bioinformatics, as well as vaccines for non-infectious indications such as cancer and opioid use disorder. Herein we review highlights from the 2
IPVC and discuss key concepts in the field of precision vaccines.
In studies involving more than 1500 African children and young adults, a conjugated group A meningococcal vaccine elicited anti–group A meningococcal antibody titers in 78% and 96% of subjects, and ...the titers were higher than those induced by the polysaccharide quadrivalent meningococcal vaccine.
For more than a century, major meningococcal meningitis epidemics have occurred every 10 to 12 years in what is known as the African meningitis belt, which stretches from Senegal to Ethiopia.
1
–
3
The majority of these epidemics have been caused by group A
Neisseria meningitidis,
and incidence rates have been as high as 500 cases per 100,000 population, with most cases occurring in persons between 1 and 29 years of age.
4
,
5
In 2009, more than 50,000 cases of group A meningococcal meningitis were reported in northern Nigeria.
6
Because of the epidemic potential and high disease burden of group A . . .
Human adenosine deaminases (ADAs) modulate the immune response: ADA1
metabolizing adenosine, a purine metabolite that inhibits pro-inflammatory and Th1 cytokine production, and the multi-functional ...ADA2, by enhancing T-cell proliferation and monocyte differentiation. Newborns are relatively deficient in ADA1 resulting in elevated plasma adenosine concentrations and a Th2/anti-inflammatory bias compared to adults. Despite the growing recognition of the role of ADAs in immune regulation, little is known about the ontogeny of ADA concentrations.
In a subgroup of the EPIC002-study, clinical data and plasma samples were collected from 540 Gambian infants at four time-points: day of birth; first week of life; one month of age; and four months of age. Concentrations of total extracellular ADA, ADA1, and ADA2 were measured by chromogenic assay and evaluated in relation to clinical data. Plasma cytokines/chemokine were measured across the first week of life and correlated to ADA concentrations.
ADA2 demonstrated a steady rise across the first months of life, while ADA1 concentration significantly decreased 0.79-fold across the first week then increased 1.4-fold by four months of life. Males demonstrated significantly higher concentrations of ADA2 (1.1-fold) than females at four months; newborns with early-term (37 to <39 weeks) and late-term (≥41 weeks) gestational age demonstrated significantly higher ADA1 at birth (1.1-fold), and those born to mothers with advanced maternal age (≥35 years) had lower plasma concentrations of ADA2 at one month (0.93-fold). Plasma ADA1 concentrations were positively correlated with plasma CXCL8 during the first week of life, while ADA2 concentrations correlated positively with TNFα, IFNγ and CXCL10, and negatively with IL-6 and CXCL8.
The ratio of plasma ADA2/ADA1 concentration increased during the first week of life, after which both ADA1 and ADA2 increased across the first four months of life suggesting a gradual development of Th1/Th2 balanced immunity. Furthermore, ADA1 and ADA2 were positively correlated with cytokines/chemokines during the first week of life. Overall, ADA isoforms demonstrate robust ontogeny in newborns and infants but further mechanistic studies are needed to clarify their roles in early life immune development and the correlations with sex, gestational age, and maternal age that were observed.
According to the World Health Organization, the entire African continent is at risk of a Zika outbreak. To increase data availability on the epidemiology of Zika virus circulation in Africa, we ...evaluated the immunity to Zika virus in a selected cohort of subjects from West Africa between 2007 and 2012. Human serum samples were collected in 2007 and in 2011/2012 from a cohort of 2-29-year-old subjects from Mali, Senegal, and The Gambia. A sample that tested positive by Zika virus IgG ELISA and by Zika virus microneutralization test was defined as positive. In 2007, the highest prevalence was 21.9%, found in Senegal among 18-29-year-old subjects. In 2011/2012, the highest prevalence, 22.7%, was found still in Senegal, but in 11-17-year-old subjects. During both study periods, the lowest prevalence was found in Mali, where few positive cases were found only in 18-29-year-old subjects. The Gambia showed an intermediate prevalence. In the three countries, prevalence was strongly associated with increasing age. This study contributes to understanding Zika virus circulation within three different ecological and demographic contexts with scarce or no data currently available. Results showed that Zika virus circulated actively in West Africa between the period 2007 and 2011/2012, but with some geographic specificity.
: The World Health Organization recommends use of a single yellow fever (YF) vaccine dose for life and fractional doses in outbreaks when there are limited vaccine stocks. In endemic regions, this ...vaccine is given as part of routine infant immunization programs around 9 months of age. There is a need to better understand immune responses when vaccinating infants particularly in contexts where the child may be malnourished.
: Data from 393 Malian and Ghanaian infants who concomitantly received measles and YF vaccines at 9 to 11 months of age were retrospectively analyzed. Response to YF vaccine was examined for association with nutritional status at time of vaccination, sex, age, pre-vaccination titers and season of vaccination.
: Neutralizing antibodies following vaccination were unaffected by season of vaccination, sex, pre-vaccination titers or nutritional status, though there was a trend to higher titers in males and children with higher height for age z-scores. Seroconversion rates differed significantly between countries (63.5 in Ghana vs. 91.0% in Mali).
: Longitudinal, prospective studies are needed to optimize the use of YF vaccine in infants in endemic settings. There may be a need for booster vaccinations and to compare various vaccine preparations to optimize the use of available vaccines.
Although effective live attenuated yellow fever (YF) vaccines have been available for over 9 decades sporadic outbreaks continue to occur in endemic regions. These may be linked to several factors ...including epidemiological factors such as vector and intermediate host distribution or vaccine coverage and efficacy. The World Health Organization's research priorities include gathering systematic evidence around the potential need for booster vaccination with YF vaccine whether this follows full or fractional doses in children. Knowledge on the longevity of response to YF vaccine and the implications of this response needs to be consolidated to guide future vaccination policy.
We measured anti-YF IgG by microneutralization assay in a group of 481 African infants who had received YF vaccine as part of routine EPI programmes, to explore serological protection from YF 5-6 years post YF vaccination, as well as the effect of co variates.
Notably, 22.2% of the cohort had undetectable antibody concentrations, with another 7.5% revealing concentrations below the threshold of seropositivity of 0.5 IU/mL. Sex, season, country and time since vaccination did not affect the longevity of antibody concentration or having antibody concentrations above a defined threshold.
Roughly 30% of children in this cohort did not demonstrate anti-yellow fever antibody concentrations above the defined threshold of protection, with 20% having no demonstrable antibody. Knowledge on the longevity of response to YF vaccine and the implications needs to be consolidated to guide future vaccination policy.
A single birth-dose of Hepatitis B vaccine (HepB) can protect newborns from acquiring Hepatitis B infection through vertical transmission, though several follow-up doses are required to induce ...long-lived protection. In addition to stimulating antibodies, a birth-dose of HepB might also induce polyfunctional CD4
T-cells, which may contribute to initial protection. We investigated whether vaccination with HepB in the first week of life induced detectable antigen-specific CD4
T-cells after only a single dose and following completion of the entire HepB vaccine schedule (3 doses). Using HBsAg- stimulated peripheral blood mononuclear cells from 344 infants, we detected increased populations of antigen-specific polyfunctional CD154
IL-2
TNFα
CD4
T-cells following a single birth-dose of HepB in a proportion of infants. Frequencies of polyfunctional T-cells increased following the completion of the HepB schedule but increases in the proportion of responders as compared to following only one dose was marginal. Polyfunctional T-cells correlated positively with serum antibody titres following the birth dose (day30) and completion of the 3-dose primary HepB vaccine series (day 128). These data indicate that a single birth dose of HepB provides immune priming for both antigen-specific B- and T cells.
Neonates have heightened susceptibility to infections. The biological mechanisms are incompletely understood but thought to be related to age-specific adaptations in immunity due to resource ...constraints during immune system development and growth. We present here an extended analysis of our proteomics study of peripheral blood-plasma from a study of healthy full-term newborns delivered vaginally, collected at the day of birth and on day of life (DOL) 1, 3, or 7, to cover the first week of life. The plasma proteome was characterized by LC-MS using our established 96-well plate format plasma proteomics platform. We found increasing acute phase proteins and a reduction of respective inhibitors on DOL1. Focusing on the complement system, we found increased plasma concentrations of all major components of the classical complement pathway and the membrane attack complex (MAC) from birth onward, except C7 which seems to have near adult levels at birth. In contrast, components of the lectin and alternative complement pathways mainly decreased. A comparison to whole blood messenger RNA (mRNA) levels enabled characterization of mRNA and protein levels in parallel, and for 23 of the 30 monitored complement proteins, the whole blood transcript information by itself was not reflective of the plasma protein levels or dynamics during the first week of life. Analysis of immunoglobulin (Ig) mRNA and protein levels revealed that IgM levels and synthesis increased, while the plasma concentrations of maternally transferred IgG1-4 decreased in accordance with their
half-lives. The neonatal plasma ratio of IgG1 to IgG2-4 was increased compared to adult values, demonstrating a highly efficient IgG1 transplacental transfer process. Partial compensation for maternal IgG degradation was achieved by endogenous synthesis of the IgG1 subtype which increased with DOL. The findings were validated in a geographically distinct cohort, demonstrating a consistent developmental trajectory of the newborn's immune system over the first week of human life across continents. Our findings indicate that the classical complement pathway is central for newborn immunity and our approach to characterize the plasma proteome in parallel with the transcriptome will provide crucial insight in immune ontogeny and inform new approaches to prevent and treat diseases.
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