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Journal of Virology, September 2005, p. 11724-11733, Vol. 79, No. 18
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.18.11724-11733.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Vaccinia Virus H3L Envelope Protein Is a Major Target of Neutralizing Antibodies in Humans and Elicits Protection against Lethal Challenge in Mice

D. Huw Davies,1 Megan M. McCausland,2 Conrad Valdez,1 Devan Huynh,1 Jenny E. Hernandez,1 Yunxiang Mu,1 Siddiqua Hirst,1 Luis Villarreal,1 Philip L. Felgner,1* and Shane Crotty2*

Center for Virus Research, Department of Molecular Biology and Biochemistry, McGaugh Hall, University of California, Irvine, California 92697,1 La Jolla Institute for Allergy and Immunology, 10355 Science Center Dr., San Diego, California 921212

Received 10 March 2005/ Accepted 15 June 2005

The smallpox vaccine is the prototypic vaccine, yet the viral targets critical for vaccine-mediated protection remain unclear in humans. We have produced protein microarrays of a near-complete vaccinia proteome and used them to determine the major antigen specificities of the human humoral immune response to the smallpox vaccine (Dryvax). H3L, an intracellular mature virion envelope protein, was consistently recognized by high-titer antibodies in the majority of human donors, particularly after secondary immunization. We then focused on examining H3L as a valuable human antibody target. Purified human anti-H3L antibodies exhibited substantial vaccinia virus-neutralizing activity in vitro (50% plaque reduction neutralization test [PRNT50] = 44 µg/ml). Mice also make an immunodominant antibody response to H3L after vaccination with vaccinia virus, as determined by vaccinia virus protein microarray. Mice were immunized with recombinant H3L protein to examine H3L-specific antibody responses in greater detail. H3L-immunized mice developed high-titer vaccinia virus-neutralizing antibodies (mean PRNT50 = 1:3,760). Importantly, H3L-immunized mice were subsequently protected against lethal intranasal challenges with 1 or 5 50% lethal doses (LD50) of pathogenic vaccinia virus strain WR, demonstrating the in vivo value of an anti-H3L response. To formally demonstrate that neutralizing anti-H3L antibodies are protective in vivo, we performed anti-H3L serum passive-transfer experiments. Mice receiving H3L-neutralizing antiserum were protected from a lethal challenge with 3 LD50 of vaccinia virus strain WR (5/10 versus 0/10; P < 0.02). Together, these data show that H3L is a major target of the human anti-poxvirus antibody response and is likely to be a key contributor to protection against poxvirus infection and disease.

* Corresponding author. Mailing address for S. Crotty: 10355 Science Center Dr., San Diego, CA 92121. Phone: (858) 678-4559. Fax: (858) 558-3525. E-mail: shane{at}liai.org. Mailing address for P. Felgner: 3221 McGaugh Hall, Irvine, CA 92697. Phone: (949) 824-1407. Fax: (949) 824-9437. E-mail: pfelgner{at}uci.edu.

Journal of Virology, September 2005, p. 11724-11733, Vol. 79, No. 18
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.18.11724-11733.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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