Preterm infants immunization

Abstract

Preterm infants have a unique immune system and a higher risk of vaccine preventable diseases. In some instances they are recommended to have additional doses of particular vaccines. This review details these preterm infants' immunization recommendations and outlines some of the strategies that can be employed to optimize their protection from vaccine preventable diseases.

Introduction

Preterm and low birth weight infants are at increased risk of hospitalization as well as morbidity and mortality from vaccine preventable diseases (VPDs). There is therefore a need to optimize protection from these diseases, which include for example invasive pneumococcal disease (IPD); haemophilus influenzae type b (Hib) and pertussis (whooping cough). In some instances preterm (defined as infants born <37 weeks gestation) or low birth weight infants (<2000 g) may not respond as immunogenically to vaccines as healthy term normal birth weight infants. The current recommendations are a balance between recognizing these potentially lower immune responses and ensuring one of the highest risk groups for VPDs are protected as early as possible (Table 1). Hence completing the primary routine vaccines at chronological age is important and additional doses may be recommended, as detailed by disease below.

Timeliness of vaccine delivery for preterm infants, optimizing protection through immunization of family members and monitoring for potential adverse events following immunization (AEFI) are all part of comprehensive immunization strategy for this vulnerable population.

The study of response to vaccines in preterm infants has enhanced the knowledge of neonatal immunology for both adaptive and innate responses. This in turn has led to a better understanding of how best to use vaccines and optimize protection of preterm infants. A detailed description of preterm infants immunology and response to vaccines is beyond the scope of this article, but in broad terms the immune response elicited early in life is different from that of a mature adult. Whilst neonates do generate both B and T cell responses, there is a true immaturity of these immune cells and they are more affected with decreasing gestational age. The result is that the preterm infant, particularly those <28–32 weeks gestation, have a physiological immunodeficiency. In addition this in the setting of the neonate's unique microenvironment, with physiological demands placed on the immune system as they transition from the usually sterile in-utero environment to the antigen rich outside world where the skin and gastrointestinal tract undergo primary colonization. The neonate is also exposed to bacteria and viruses in early life and multiple factors have been implicated, in the development of these adaptive and innate immune responses. These include: immaturity of the spleen, limited availability of complement; a lower number of plasma cells in the bone marrow and suboptimal antigen presenting cell (APC)/T cell interaction, moderated by Interferon 2 and α. The relative bias against T-helper 1 (TH1) cell polarizing cytokines also has also been implicated.

Maternal immunoglobulins (predominantly IgG subclasses 1 & 2) also play a role in protection from VPDs in the neonate. These IgG immunoglobulins are actively transported predominantly in the latter half of the third trimester, with the levels estimated to rise by approximately 5–10% with each additional week of completed gestation between 24 and 32 weeks. Extremely preterm infants receive only a fraction of the usual maternal antibodies compared to full-term infants and are often hypogammaglobulinemic.

Whilst these maternal antibodies provide some protection against VPD for the neonate, they in turn may also interfere with antibody responses to vaccines, with the impact mainly on B cell rather than T cell responses. These antibodies may thus interfere with the immunogenicity, particularly of live-attenuated vaccines, with measles immunization, for example, not recommended before the age of 6–9 months.

Another area of increasing interest in the neonatal immune response to vaccines is Toll-like receptors (TLRs), which are innate immune molecules that detect the presence of microbes. TLRs have a unique expression profile in the neonate and their activation leads not only to the induction of inflammatory responses but also to the development of antigen-specific adaptive immunity. The use of certain TLR agonists as neonatal vaccine adjuvants is a current area of active research.

Immune memory is also important in vaccines producing long lasting protection and this does not seem to be as affected by prematurity. A primary course of vaccines in the first year of life is a good priming for immune memory, which can be induced by giving a ‘booster’ vaccine dose at >12 months of age, for example with the conjugate vaccines such as Hib and meningococcal C.

To maximize their protection preterm infants, should be immunized according to chronological age rather than gestational age and only true contraindications to vaccination delaying their administration. Timeliness of vaccine administration is crucial for direct protective effects during infancy and early childhood and it applies to both term and preterm infants. Studies have found that low birth weight is at significantly greater risk of immunization delays during the first year of life. Factors that may influence timeliness of vaccine delivery in preterm infants include parental confusion about vaccination being on gestational rather than corrected age and the perception of preterm infants as being fragile. Parental attitude towards childhood vaccinations can also be a barrier as some have concerns about vaccine effectiveness and safety. There is good evidence that infants are capable of generating protective immune responses to multiple vaccines given concurrently, but studies have shown parents are often concerned their preterm infant is not developed enough and might be overwhelmed by receiving multiple vaccines at once. This leaves these vulnerable infants at higher risk of vaccine preventable diseases have a high level of morbidity and mortality in the first year of life such as invasive pneumococcal disease and pertussis.

Educating neonatologists about vaccines and current recommendation, plus the evidence-base behind these guidelines for preterm infants, is essential if their immunization status is going to be optimized. Physician recommendation can have a critical impact on the immunization status of children, with studies on influenza vaccine finding much higher vaccination rates if a physician had recommended it.