A recombinant vaccine expressed in the milk of transgenic mice protects Aotus monkeys from a lethal challenge with Plasmodium falciparum

被引:79
作者
Stowers, AW
Chen, LH
Zhang, YL
Kennedy, MC
Zou, LL
Lambert, L
Rice, TJ
Kaslow, DC
Saul, A
Long, CA
Meade, H
Miller, LH
机构
[1] NIAID, Lab Parasit Dis, Malaria Vaccine Dev Unit, Rockville, MD 20852 USA
[2] Genzyme Transgen Corp, Framingham, MA 01701 USA
关键词
D O I
10.1073/pnas.012590199
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Two strains of transgenic mice have been generated that secrete into their milk a malaria vaccine candidate, the 42-kDa C-terminal portion of Plasmodium falciparum merozoite surface protein 1 (MSP1(42)). One strain secretes an MSP1(42) with an amino acid sequence homologous to that of the FVO parasite line, the other an MSP1(42) where two putative N-linked glycosylation sites in the FVO sequence have been removed. Both forms of MSP1(42) were purified from whole milk to greater than 91% homogeneity at high yields. Both proteins are recognized by a panel of monoclonal antibodies and have identical N termini, but are clearly distinguishable by some biochemical properties. These two antigens were each emulsified with Freund's adjuvant and used to vaccinate Aotus nancymai monkeys, before challenge with the homologous A falciparum FVO parasite line. Vaccination with a positive control molecule, a glycosylated form Of MSP1(42) produced in the baculovirus expression system, successfully protected five of six monkeys. By contrast, vaccination with the glycosylated version of milk-derived MSP1(42) conferred no protection compared with an adjuvant control. Vaccination with the nonglycosylated, milk-derived MSP1(42) successfully protected the monkeys, with 4/5 animals able to control an otherwise lethal infection with P. falciparum compared with 1/7 control animals. Analysis of the different vaccines used suggested that the differing nature of the glycosylation patterns may have played a critical role in determining efficacy. This study demonstrates the potential for producing efficacious malarial vaccines in transgenic animals.
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页码:339 / 344
页数:6
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