Immunization with DNA vaccines in early life: Advantages and limitations as compared to conventional vaccines

Abstract

The need for early life immunizationNeonatal or early infant immunizations are required to give protection from diseases caused by pathogens to which exposure occurs in early life. As an example, the median age of infants with a respiratory syncytial virus (RSV) infection severe enough to require hospitalization is below 3 months of age worldwide. A significant proportion of severe early infections are due either to encapsulated bacteria such as Haemophilus influenzae, Streptococcus pneumoniae, or Neisseria meningitidis or to intracellular agents such as viruses [RSV, measles virus (MV), rotavirus, herpes simplex viruses, cytomegalovirus], certain bacteria (Listeria monocytogenes, salmonella, mycobacteria) or other microorganisms (Chlamydiae, Ureaplasma). This enhanced susceptibility of newborns and infants to specific infectious diseases is due to limitations of both their innate and specific immune system. Immune responses in early life differ from adult responsesThe impaired function of monocytes/macrophages in newborns has been associated with reduced expression of major histocompatibility complex (MHC) class II and costimulatory molecules, decreased antigen-processing capacity and altered cytokine production. Although little is known about the development of human dendritic cells, their maturation appears to be slow and their function as antigen-presenting cells (APC) is rather poor at birth [10], thus probably contributing to the limitations of the induction of specific immune responses. Although natural killer (NK) cells are present in significant numbers at birth, their functional activity [reflected by interferon-y (IFN-y) production and NK cell-mediated lysis] also remains low for several weeks. It is not yet known precisely which part of these limitations reflects the intrinsic immaturity of infant NK cells or their impaired activation by cytokines or factors that prevail in the Correspondence to." C.-A. Siegrist

CpG DNA can induce strong Th1 humoral and cell-mediated immune responses against hepatitis B surface antigen in young mice

“…Quantitative differences included a slower rate of appearance of antibodies and lower peak titers, except for DNA vaccines where all ages had similar peak titers, in agreement with other reports (17,52,53). The relatively high titers at young ages with the DNA vaccine probably are related to the longevity of antigen expression and efficient antigen presentation.…”

“…The Th2 bias of the immature immune system is thought to be a result of antigen presentation by APC with inadequate costimulation, different functioning of T cells upon antigen stimulation, lower efficiency of neonatal APC, and fewer T cells and APC (17,19,(52)(53)(54). As such, antigen load, antigen persistence, and ''danger signals'' that induce costimulatory activity can have an influence (12,55).…”

CpG ODN can re-direct the Th bias of established Th2 immune responses in adult and young mice

“…Neonatal immune responses are known to be intrinsically Th2 biased [36]. This is thought to be due to the decreased number and functional capacity of APC, decreased functional activity of natural killer cells which results in reduced IFN-Q levels, decreased number and altered function of CD4 cells (i.e., their hypo-responsiveness to IL-12, hyper-responsiveness to IL-4 and decreased expression of CD40 ligand) [37]. Although several reports have shown that, by using CpG ODN as an adjuvant, it is possible to circumvent the Th2 bias of neo-natal immune responses, it has not been possible to skew a neonatally primed Th2 response away from its Th2 bias [38].…”

Immune Responses following Neonatal DNA Vaccination Are Long-Lived, Abundant, and Qualitatively Similar to Those Induced by Conventional Immunization

“…Killed vaccines, although safer, often do not stimulate the strong responses necessary to provide long-lived protective immunity, and they are rather ineffective in stimulating the CD8 ϩ T-cell responses which are critical for protection against a wide variety of intracellular pathogens. In addition, numerous examples indicate that neonates and adults may respond differently to immunological challenges (33). For these reasons, few vaccines are given in the neonatal period; most are withheld until infancy, and repeated booster immunizations are administered throughout infancy and early childhood to ensure adequate levels of protection.…”