RECOMBINANT BCG T CELL PRIMING AGAINST MEASLES

Project Details

Description

Measles is the major childhood cause of death in the world attributable to
a single cause. The overall objective of this proposal is to develop a
novel strategy to provide protection against measles infection at the
earliest time after birth with measles proteins expressed in recombinant
BCG (rBCG), which is not neutralized by maternal antibody. There is a
limit to the effectiveness of existing live attenuated measles vaccines in
infants less than 9 months of age because they are neutralized by maternal
IgG and, when given in a high-titer to overcome neutralization, are
associated with increased mortality. While it is quite clear that
antibodies against the measles conformational protective H and F proteins
are effective at neutralization, they may not be appropriately presented
in rBCG. The candidate's principal aim, then, is to attempt to prime for
memory T cells with the nucleocapsid protein or other proteins of measles
virus in the absence of production of neutralizing antibodies There are
precedents involving T and B cell recognition of influenza that support
these immunization principles. The general questions to be tested are
whether upon subsequent challenge with a vaccine booster or natural virus
infection, sufficient memory for T cell help is developed such that: 1) an
accelerated secondary type neutralizing antibody response is developed,
which if not able to prevent infection, can eliminate its serious
consequences such as neurological damage and death; and 2) whether
development of cytotoxic and lymphokine-producing T cells is sufficient to
protect against viral disease. To test whether T cell priming with the
internal N protein of measles leads to an accelerated secondary type
antibody response to the protective conformational H and F epitopes after
challenge with measles virus, rBCG::measles N primed mice will be
challenged with intact virions and the kinetics of appearance of serum
measles HAI and neutralizing antibody titers will be measured. In a
similar manner, H and F antibody responses I.n mice primed with
rBCG::measles H and F constructs will be studied. To determine whether
rBCG measles constructs engage T cells in a manner that will elicit a
protective immune response, measles-susceptible strains of mice (in which
measles protection is largely cell-mediated) will be challenged with the
rodent-adapted/CAM measles virus. In vitro measles purified N and whole
virion-specific T cell proliferation, cytotoxic activity, and cytokine and
lymphokine production will be determined along with viral titers and
histopathology. Finally, the ability of beagles and cynomolgus monkeys
vaccinated with rBCG::measles protein strains at a time when they have
circulating maternally-acquired measles neutralizing antibody to later
mount a protective immune response to either canine distemper virus (CDV),
(a closely related Morbillivirus) or to virulent measles virus will be
studied.
StatusFinished
Effective start/end date7/1/946/30/99

Funding

  • National Institutes of Health: $91,260.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $79,720.00

ASJC

  • Medicine(all)
  • Immunology and Microbiology(all)

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