Protection of neonates and infants by maternal immunization

KEYWORDS:

• Maternal immunization
• colostrum
• passive transfer
• pertussis
• RSV
• influenza

Neonates, infants, and pregnant women are at higher risk of succumbing to infectious diseases, with up to 600,000 neonates dying of infections annually [1]. While the neonate receives pathogen-specific immunoglobulin from the mother transplacentally and via colostrum, often the levels are not sufficiently high to provide protection for the time required for active immunity to develop. Maternal immunization is an attractive strategy to enhance immunoglobulin levels in the neonate, a practice that has been used for decades with tetanus vaccines and has been used successfully in the animal health industry for even longer as a means of preventing enteric diseases. In addition to the newborn, levels of maternal mortality and morbidity due to vaccine-preventable diseases are also higher than in nonpregnant women in the case of influenza virus infection, and thus, maternal immunization could reduce morbidity and mortality in two target populations, mother and child. Immunization of pregnant women against tetanus, influenza, and pertussis has been recommended in various countries, but there are still concerns among members of the public regarding the safety for both the mother and the fetus.

The main concerns around maternal immunization are the safety of the fetus as well as the potential interference with early childhood vaccines. Several vaccines are now recommended for immunization during the last trimester including influenza and pertussis vaccines. All of these are inactivated vaccines, each with an excellent safety profile. Thus, the risk of infection of the fetus, which could result in potential abortion and birth defects, is essentially nonexistent. However, of concern is the choice of adjuvant and the potential impact the adjuvant could have on the maternal immune system and subsequently on its interaction with the fetal immune system. During pregnancy, the maternal immune system is regulated toward a regulatory type of immune response, resulting in reduction of maternal cytotoxic T cells, which otherwise would attack paternal major histocompatibility complex molecules expressed on fetal cells [2]. Locally expressed cytokines and chemokines as well as expression of the neonatal Fc-receptor facilitate transfer of large quantities of antibodies across the placenta. In humans, such transfer across the placenta starts during pregnancy and continues after birth via colostrum and breast milk, while in other species, transfer exclusively occurs via colostrum and milk. Using potent adjuvants could affect the cytokine balance at the fetal–maternal interface, which could lead to improper suppression of maternal cytotoxic lymphocytes and subsequent attacks of fetal cells during development. Furthermore, since cytokines are found in high concentrations in the colostrum and early milk, these could also affect early development of the mucosa-associated lymphoid tissues especially in the gut, where homeostasis relies on a T helper 2 (Th2) environment. Thus, more research is needed to clearly understand the role of adjuvants during maternal immunization, particularly with respect to safety. Until then, adjuvants that promote either a balanced or Th2 type of response should be used, or as seen during the 2009–2010 H1N1 influenza pandemic, non-adjuvanted vaccines could be used with no safety concerns.

The second issue of concern is the interference with active immunization of the neonate, which can reduce the overall response to the vaccine. Several mechanisms of interference have been suggested including neutralization, epitope masking, increased activation of Fc-receptor signaling, and increased Fc-mediated phagocytosis [3,4]. In general, the higher the level of maternal antibodies, the more interference with vaccination occurs [3–5]. Evidence for this observation comes from studies in large animal species and humans using vaccines for measles, influenza, and pertussis (whooping cough), serious respiratory diseases of infants and young children [3–6]. As noted in both animal models and clinical studies in humans, maternal antibodies can provide protection against infection with Bordetella pertussis and lead to lower prevalence rates in affected cohorts [7,8]. However, protection wanes rapidly and essentially depends on the half-life of the antibodies [9]. In the case of pertussis, however, several studies have shown that when using the same type of vaccine in the mother and the infant, e.g., the acellular pertussis vaccines (aP), responses to pertussis toxoid and filamentous hemagglutinin were diminished due to the interference by maternal antibodies [10,11]. Whether this results in clinically reduced efficacy and can be overcome by additional booster immunizations is subject of further studies. Second, susceptibility of the infant is increased due to neutralization of maternal antibodies. Thus, there is a need for early-life vaccines that are effective even in the presence of maternal antibodies and that at the same time do not affect the level of protection provided by the maternal antibodies. Potential solutions include formulation of the vaccine into particles that would essentially hide the antigens from recognition by maternal antibodies until the vaccine formulation is taken up by antigen-presenting cells. Using a novel combination adjuvant consisting of polyphosphazenes, host defense peptides, and polyI:C, we were able to show that early-life vaccination was effective even in the presence of high levels of maternal antibodies [12]. Alternatively, one could use different vaccines that display different antigen repertoires, i.e., varying combinations of subunit vaccines, or whole-cell versus acellular vaccines, to ensure that interference with maternal antibodies affects neither vaccine efficacy nor protection by maternal antibodies.

Respiratory syncytial virus (RSV) is considered a prime target for maternal immunization. Hospitalization of infants due to RSV infection occurs frequently between 6 weeks and 6 months, with peak incidence at 2 to 3 months of age [13]. Young infants, specifically those 0–6 months of age, do not mount an effective immune response to RSV [14], making the development of an efficacious vaccine for this age group challenging. Maternal immunization is an attractive approach to protect this highly susceptible population and is strongly supported by the World Health Organization. Several lines of evidence support that maternal vaccination will be effective against RSV infection in infants: (i) although T cells play a role in viral clearance, neutralizing antibodies are the best correlate of protection [15]; (ii) in the very young infants, maternal antibodies are protective [16], and (iii) administration of Palivizumab, a humanized monoclonal antibody specific for a neutralizing epitope on the fusion protein, provides protection in premature and at-risk infants from RSV disease [17]. Thus, maternal immunization is expected to enhance and prolong the protective levels of RSV-specific antibodies in the infants.

In one clinical trial with a subunit, fusion protein-based, RSV vaccine, the increase in neutralizing antibody appeared to be moderate [18]. Recently, a nanoparticle-based RSV fusion protein formulated with alum induced an approximately twofold increase in serum neutralizing antibody levels to RSV and a fivefold increase in women with lower baseline levels [19]; this vaccine will be tested in advanced clinical trials in pregnant women in the near future. Three additional RSV vaccine candidates are in a phase II clinical study in healthy women of child-bearing age (http://www.clinicaltrials.org). While safety and efficacy can be established through human clinical studies, protection in animal models can provide supportive data. We demonstrated transfer of maternal antibodies from RSV subunit vaccine-immunized ewes to newborn lambs, as well as significantly reduced virus production and lung pathology in these lambs after RSV challenge [20], further supporting this approach.

In conclusion, maternal immunization has proven to be a simple and safe procedure for the protection of both the mother and the child using the limited number of vaccines currently recommended. These recommendations are being translated into routine care in many countries, but uptake need to be improved to harness the full value of this strategy.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.