1st International Neonatal and Maternal Immunization Symposium

Abstract

The 1st International Neonatal and Maternal Immunization Symposium was held in Antalya, Turkey from 26 to 28 March 2010. Delegates who attended ranged from obstetricians and pediatricians to infectious diseases and immunization specialists. Topics covered included maternal and neonatal immunology, vaccine-specific responses in neonates and pregnant women, as well as vaccine safety and future vaccine strategies. Important new and emerging themes included: first, the idea that the neonatal immune system is not immature but is appropriate for the specific age and develops over time by as yet not well defined regulatory processes; second, that neonatal mucosal immunity is important and not well defined; third, that maternal pneumococcal immunization may be protective against pneumococcal disease in early infancy; and fourth, that monovalent H1N1 2009 influenza vaccine is safe and immunogenic in pregnant women.

The incidence of many vaccine-preventable diseases is higher in early infancy and the role of immunization at birth or during pregnancy has long been of interest, but relatively few published data are available. The 1st International Neonatal and Maternal Immunization Symposium was held in Antalya, Turkey from 26 to 28 March 2010 with the aim of bringing together the diverse scientific and clinical expertise relevant to this area. Delegates included neonatalogists, obstetricians, pediatricians, and infectious diseases and immunization specialists. Topics covered included maternal and neonatal immunology, early-life vaccinology, vaccine responses to individual pathogens both in the neonate and pregnant women, vaccine safety and potential strategies for future vaccine development. The importance of this topic is illustrated by the fact that each year more than 2 million children worldwide, aged between 1 and 6 months old, die from acute respiratory infections or diarrhea-related diseases, many of which are potentially vaccine preventable. Up to half of these deaths are due to infectious diseases, such as Gram-negative pathogens, Group A and B Streptococcus, Pneumococcus and Staphylococcus aureus. In addition, there is evidence that the neonatal mortality rate is systematically underestimated in many of the high-mortality areas of the world. At present only three vaccines are given at birth, oral polio vaccine, hepatitis B and bacillus Calmette–Guérin, and concerns remain about vaccination during pregnancy. In addition, concerns regarding immune tolerance and adverse events have hindered the development of neonatal vaccination as a strategy. The aim of the 1st International Neonatal and Maternal Immunization Symposium was to increase knowledge of the development and function of the neonatal immune system, how maternal immunity and immunization protects and influences neonatal vaccine responses and to use this knowledge to develop new and more effective vaccine strategies for preventing neonatal deaths. This short report summarizes several of the important and new themes that emerged from the symposium that are of relevance for obstetricians and neonatologists.

Neonatal immune system is not immature

The neonatal immune system has long been considered to be ‘immature’ and less able to respond to antigens, such as vaccines, compared with older infants and children. However, increasing knowledge suggests that the neonatal immune system is not immature but rather appropriate for early postnatal life, developing over time by as yet not well-defined regulatory processes. Tobias Kollman (University of British Columbia, BC, Canada) introduced the neonatal immune system in his presentation “Development of the innate immune system of the human newborn”. The neonatal immune response to Toll-like receptor (TLR) agonists (agonists include a range of chemicals that stimulate the TLRs) suggests that Th17- and Th2-type immunity, which promote defence against extracellular pathogens, is well developed, but that there is a reduced capacity to support Th1-type responses, which promote defence against intracellular pathogens. This explains the susceptibility of the neonate to intracellular pathogens, such as the bacterium Listeria and herpes viruses. The development of neonate and infant T-cell responses has been recently examined in a study of Gambian infants and was discussed by Sarah Burl (MRC Laboratories, Gambia) in the presentation “Responses to Toll like receptor (TLR) agonists in early life”. T-cell cytokine responses to ten TLR agonists were examined at birth (cord blood) and at 1, 2, 3, 4, 6, 9 and 12 months of age. Responses to TLR agonists 2, 4, 5, 7 and 8 were detected in cord blood but at low levels. However, by 1 month of age, TNF-α and IFN-γ responses to agonists were greater than in cord blood and remained at similar levels for 12 months. By contrast, IL-6 levels to most agonists were high at birth and remained so until 12 months of age. These data suggest that cytokine responses mature rapidly between birth and 1 month of age and provide valuable background information to inform the development of TLR agonists as potential adjuvants for infant vaccines.

Neonatal mucosal immunity is important & not well defined

An important area for future research and vaccine development is neonatal mucosal immunity. Pearay Ogra, from the Children’s Hospital, Buffalo (NY, USA), one of the world’s senior mucosal immunologists, presented on “Mucosal immunology in the neonatal period.” The neonatal mucosal adaptive immunity includes the inductive sites such as Peyer’s patches and organized lymphoid follicular structures in the gastrointestinal (gut-associated lymphoid tissue) and respiratory tracts, nasopharyngeal and sublingual tissues and the skin. The effector sites include the lamina propria, submucosa and intraepithelial sites. Peyer’s patches are first observed around 10–11 weeks of gestation. By 20–30 weeks of gestation, up to 50–90 patches with well-defined B- and T-cell zones containing CD5⁺ and IgA⁺ B cells, and HLA-DR⁺, CD4⁺ T cells, are found. Activated B cells, mostly IgA, are detected in the mucosal tissues shortly after birth. However, IgA-producing plasma cells are not generally detected in the mucosa before 10 days of age. With progressive environmental antigenic stimulation, the number of circulating IgA cells increases significantly by 1 month of age. The postnatal development of mucosal immunity is critically influenced by the acquisition, temporal pattern, qualitative and quantitative aspects of mucosal microflora, and the nature of dietary antigens and other environmental agents introduced in the neonatal period. A better understanding of how this occurs is needed for future mucosal vaccine development.

Reduced placental transfer of maternal antibody to the fetus, in mothers with vaccine-acquired rather than natural immunity, impacts on the timing of administration of live viral vaccines in infants

Placental transfer of antibodies (mother to fetus) has been shown to protect newborns and infants. The amount of antibody transferred is dependent on several factors, including gestational age and maternal antibody level. Antibodies have been shown to interfere with the infant immune response to certain vaccines, such as measles. With increasing age of mothers, reduced natural infection rates and increasing time since childhood booster vaccines, cohorts of pregnant women with lower levels of maternal antibody levels and subsequent placental transfer may mean reduced protection in infancy, and necessitate earlier administration of some vaccines, such as measles. In a prospective cohort study in Belgium (2006–2008) presented by Elke Leuridan (University of Antwerp, Belgium), the kinetics and persistence of maternal antibodies against measles, mumps, rubella and varicella in 221 woman–child pairs was examined. Presence of maternal antibodies against measles persisted on average longer in infants born to mothers with a history of natural measles infection versus vaccinated women (3.78 vs 1.80 months). Similar durations of passive immunity were observed for rubella (2.6 months) and varicella (3.25 months). These findings suggest that earlier measles administration, possibly prior to 6 months of age, may be required.

Infants in neonatal intensive care units experience fever & apnea post-immunization but are not likely to have increased evaluation for sepsis

One of the concerns of neonatologists is increased fever, apnea and bradycardia following vaccination of premature infants and subsequent need for sepsis evaluation due to fever or increase in ventilatory requirements. The US Advisory Committee on Immunization Practices recommends vaccination of premature infants at the recommended time according to chronological age and not corrected age. Neal Halsey (John Hopkins Bloomberg School of Public Health, MD, USA) presented an overview of recent data on adverse events following vaccination of premature infants in his presentation “Safety issues associated with early immunization”. A study of 490 infants in neonatal intensive care units in the Kaiser Permanente Medical Care Program examined whether vaccination resulted in increased need for sepsis evaluation. An increased rate of fever and cardiorespiratory events after immunization was observed. However, routine vaccination was not associated with increased risk of receiving a sepsis evaluation. Halsey concluded that providers may be deferring immunizations until infants are clinically stable, or may have a higher threshold for initiating sepsis evaluations after immunization than at other times.

These findings have recently been published in the Journal of Perinatology[1].

Maternal pneumococcal immunization may be protective against pneumococcal disease in early infancy

Two recent studies suggest that maternal pneumococcal (PNC) immunization may protect infants from PNC disease in early infancy. Emma Holmlund (National Public Health Institute, Helsinki, Finland) presented on the “Persistence of maternal antibodies after immunization of Filippino pregnant women with PNC polysaccharide (PS) vaccine and immunogenicity of PNC PS in infants and toddlers”. In this randomized controlled maternal immunization study, infants of 106 pregnant Filipino women vaccinated with PNC PS demonstrated longer antibody persistence compared with infants of unvaccinated mothers. Antibody responses were statistically significantly higher in the infants of vaccinated mothers at 3 months old for serotypes 6B and 19F and at 4 months for serotypes 14 and 18C compared with infants of unvaccinated mothers. In addition, despite the presence of maternal antibody there was no hyporesponsiveness seen following infant vaccination with PNC PS vaccine. Deborah Lehmann (Telethon Institute for Child Health Research, Perth, Australia) presented “Pneumococcal serotype specific antibody in indigenous Australian women and infants enrolled in a maternal vaccination trial (PNEUMUM)” on behalf of Sarah Moberley (Menzies School of Health Research, Darwin, Australia). Indigenous women were randomized to receive PNC PS vaccine during pregnancy, at delivery or postnatally. Higher cord anti-PNC antibodies were found in infants of mothers vaccinated during pregnancy (21 PNC serotypes) compared with infants of mothers given PNC PS at delivery and no hyporesponsiveness following infant vaccination was noted. Importantly, this study explored IgA levels in expressed breast milk. At delivery, expressed breast milk serotype-specific IgA geometric mean concentrations and antibody avidity were consistently higher in participants who had been vaccinated during pregnancy compared with unvaccinated participants for all serotypes (p ≤ 0.05 for serotype 1, 7F, 9V, 12F and 22F). Expressed breast milk IgA antibody levels and avidity (suggesting functional immunity) were higher in women given the 23vPPV during pregnancy compared with 23vPPV at delivery; however, the mechanism for this is not known. Data on whether higher antibody levels reduce PNC infection or colonization in infants are not yet available.

Monovalent H1N1 2009 influenza vaccine is safe & immunogenic in pregnant women

Kathy Edwards (Vanderbilt University, TX, USA) presented “H1N1 vaccines during pregnancy”. An unadjuvanted subvirion 2009 H1N1 influenza vaccine was given to 120 women in the second or third trimester of pregnancy. Participants were randomly assigned to receive a H1N1 09 vaccine containing either 15 or 30 µg of hemagglutinin antigen as a two-dose series, 21 days apart. Serum samples obtained at baseline, prior to the second vaccine and 21 days after the second vaccination were tested for H1 antibody by a hemagglutination inhibition assay. Following the first vaccination, antibody titers of 1:40 or greater were detected in 93% of subjects who received the 15-µg vaccine and 97% of subjects who received the 30-µg vaccine. In both groups the geometric mean titers peaked following the first vaccination and did not increase further following the second vaccination. The H1N1 09 vaccine was well tolerated and there were no adverse neonatal outcomes related to vaccination. These data suggest that a single dose of an inactivated 2009 H1N1 vaccine containing 15 µg of hemagglutinin antigen is safe and immunogenic, and likely to be protective against influenza in pregnant women, supporting immunization recommendations during the 2010 influenza season.

Can maternal vaccination prevent neonatal herpes simplex infection?

Mark Shleiss (University of Minnesota, MN, USA) presented on “Cytomegalovirus vaccines” and included recent data on herpes simplex virus (HSV) vaccine development. Maternal HSV infection is well known to cause congenital and perinatal transmission to the fetus and newborn infant; however, there is a lack of understanding of correlates of protective immunity for both the mother and the fetus and this has hindered vaccine development. Herpes viruses encode multiple immune evasion genes, and are able to establish lifelong, persistent infection in the host. Recent strategies undergoing evaluation in clinical trials include both the approach of attenuated live-virus vaccines as well as recombinant, subunit vaccines that target immunodominant virally encoded proteins. A recombinant subunit vaccine against genital HSV infection, based on the viral glycoprotein gD, has demonstrated efficacy in placebo-controlled studies, and merits further investigation. Several trials have been conducted in mouse models. In terms of efficacy, it is assumed that successful immunization to prevent genital HSV is therefore likely to prevent neonatal HSV infection, although this end point may be difficult to demonstrate in clinical trials.

Overall the 1st International Neonatal and Maternal Immunization Symposium included presentations from internationally recognized experts, highlighted recent advances in understanding neonatal immunology and vaccine development and the many unanswered questions relating to how to best use vaccines during pregnancy and in the neonatal period. Neonatal and maternal immunization is likely to be increasingly important in the coming years, with research in this area moving into clinical and public health practice. The support of obstetricians will be vital in making this a reality.

Financial & competing interests disclosure

Nicholas Wood was a recipient of the European Clinical Society for Microbiology and Infectious Diseases (ECSMID) travel grant to attend the symposium. The 1st International Neonatal and Maternal Immunization Symposium was supported by the European Society of Pediatric Infectious Diseases (ESPID), the European Clinical Society for Microbiology and infectious Diseases (ECSMID) and the Turkish Pediatric Society. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.