A recombinant vaccine expressed in the milk of transgenic mice protects Aotus monkeys from a lethal challenge with Plasmodium falciparum.
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 P. 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.
Stowers
Anthony W
AW
Malaria Vaccine Development Unit, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Rockville, MD 20852, USA. astowers@niaid.nih.gov
Chen Lh
Li-how
LH
Zhang
Yanling
Y
Kennedy
Michael C
MC
Zou
Lanling
L
Lambert
Lynn
L
Rice
Timothy J
TJ
Kaslow
David C
DC
Saul
Allan
A
Long
Carole A
CA
Meade
Harry
H
Miller
Louis H
LH
D000595:Amino Acid Sequence; D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood; D000941:Antigens / Q000737:chemistry; D001029:Aotus trivirgatus / Q000469:parasitology*; D006031:Glycosylation; D017780:Malaria Vaccines / Q000627:therapeutic use*; D016778:Malaria, Falciparum / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D008892:Milk / Q000378:metabolism*; D008969:Molecular Sequence Data; D010963:Plasmodium falciparum / Q000472:pathogenicity*; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000378:metabolism; D013997:Time Factors; D019444:Vaccines, DNA / Q000378:metabolism*
D000913:Antibodies, Protozoan; D000941:Antigens; D017780:Malaria Vaccines; D011994:Recombinant Proteins; D019444:Vaccines, DNA