Induction of neonatal tolerance by plasmid DNA vaccination of mice.

Abstract

Plasmid DNA vaccines capable of preventing viral, bacterial, and parasitic infections are currently under development. Our labs have shown that a plasmid DNA vaccine encoding the circumsporozoite protein of the malaria parasite elicits protective immunity against live sporozoite challenge in adult BALB/c mice. We now find that the same DNA vaccine induces tolerance rather than immunity when administered to 2-5 d-old mice. Neonatally tolerized animals were unable to mount antibody, cytokine or cytotoxic responses when rechallenged with DNA vaccine in vitro or in vivo. Tolerance was specific for immunogenic epitopes expressed by the vaccine-encoded, endogenously produced antigen. Mice challenged with exogenous circumsporozoite protein produced antibodies against a different set of epitopes, and were not tolerized. These findings demonstrate important differences in the nature and specificity of the immune response elicited by DNA vaccines versus conventional protein immunogens. ( J. Clin. Invest. 1996. 98: 2700-2705.)

Oral DNA Vaccination In Utero Induces Mucosal Immunity and Immune Memory in the Neonate

“…The induction of immune tolerance is thought to be a potential risk when immunizing fetuses and newborns with a DNA vaccine (51,52). There are numerous reports, however, of successful DNA immunization in neonates of several species, including mice (53-59), rats (60), sheep (9), pigs (61,62), chimpanzees (63,64), and baboons (65,66).…”

“…There are numerous reports, however, of successful DNA immunization in neonates of several species, including mice (53-59), rats (60), sheep (9), pigs (61,62), chimpanzees (63,64), and baboons (65,66). To date, only immunization with a plasmid DNA, encoding the circumsporozoite protein of Plasmodium yoelii, induced nonresponsiveness in newborn mice (51,52). This neonatal tolerance, however, was prevented by coadministration of plasmid-encoding GM-CSF (53).…”

Preclinical and Clinical Safety Studies on DNA Vaccines

“…46 Vaccination of 2-6-month-old mice with a DNA vaccine encoding the circumsporozoite protein (pCSP) of malaria resulted in immunity. However, neonatal mice of different MHC types and younger than seven days of age did not develop a serum antibody response, 47,48 and remained unresponsive when revaccinated as adults. 48 The tolerance induced by early vaccination was antigenspecific, as it was not induced by DNA plasmids encoding other malaria proteins, 36 or by DNA vaccines against other infectious diseases.…”

“…However, neonatal mice of different MHC types and younger than seven days of age did not develop a serum antibody response, 47,48 and remained unresponsive when revaccinated as adults. 48 The tolerance induced by early vaccination was antigenspecific, as it was not induced by DNA plasmids encoding other malaria proteins, 36 or by DNA vaccines against other infectious diseases. 49,50 However, the examples above show that safety testing of each new DNA vaccine that will be used in children or newborns is extremely important.…”

Diabetes tolerogenic vaccines targeting antigen-specific inflammation

“…39 Besides the mucosal tolerance and SIT, more attractive approaches to achieve tolerogenic responses and induce antigen specific suppression have emerged in recent years 14,27,[40][41][42][43][44] (Fig. 2).…”