Important note: Information in this article was accurate in August 1999. The state of the art may have changed since the publication date.AIDSWEEKLY Plus; Monday, August 30, 1999
Daniel J. DeNoon, Senior Editor
CW HENDERSON PUBLISHER -- A new prime/boost vaccine regimen efficiently induces specific cytotoxic lymphocyte (CTL) responses in the rhesus monkey model of AIDS.
The majority of AIDS researchers believe that an effective HIV vaccine must elicit cytotoxic lymphocytes (CTLs). The new regimen achieves exactly that.
However, only one of three vaccinated animals fully resisted infection after challenge with a highly pathogenic strain of simian immunodeficiency virus (SIV).
The new regimen uses DNA plasmids encoding multiple CTL epitopes on the SIV Gag protein. After priming vaccinations with the DNA plasmids, the animals received boosting vaccinations with modified vaccinia virus Ankara (MVA) containing the same Gag epitopes.
"The present study does not attempt to define correlates of protective immunity nor design a protective vaccine against immunodeficiency viruses, but it demonstrates clearly that the DNA prime-MVA boost regimen is an effective protocol for induction of CTLs in macaques," wrote Tomas Hanke of the University of Oxford, U.K., and colleagues.
"It also shows that powerful tools for studying the role of CTLs in the control of SIV and human immunodeficiency virus [HIV] infections are now available."
Hanke et al. reported their findings in the Journal of Virology ("Effective Induction of Simian Immunodeficiency Virus-Specific Cytotoxic T Lymphocytes in Macaques by Using a Multiepitope Gene and DNA Prime-Modified Vaccinia Virus Ankara Boost Vaccination Regimen," J Virol 1999 Sep;73(9):7524-32
There was no clear correlation between the ability of the vaccine regimen to induce CTLs and protection against challenge with the highly infectious SIVmac251 strain. But CTLs are not expected to prevent initial infection.
"In vivo, CTLs may be able to clear the initial small number of infected cells before HIV spreads further and establishes generalized infection," Hanke et al. wrote. "This might explain detection of HIV specific CTL responses in exposed but uninfected commercial sex workers whose cells were fully susceptible to infection with HIV, in uninfected infants born to HIV infected mothers, and seronegative health care workers occupationally exposed to HIV contaminated body fluids."
The immunogen used in the vaccine was a string of SIV and HIV derived proteins recognized by murine, macaque, and human CTLs.
Interestingly, one of four control animals vaccinated with MVA also remained uninfected after challenge with SIVmac251.
"Taken together, these results suggest that MVA may induce a non-specific antiviral effect, the mechanism of which is currently under investigation," Hanke et al. wrote. "Although for use in humans determination of the underlying mechanisms would be comforting, the antiviral effects of MVA are generally welcome."
At this year's Retrovirus conference, Vanessa Hirsch of the U.S. National Institute of Allergy and Infectious Diseases extolled the virtues of MKA as a vector for AIDS vaccines.
"We believe that this is a very promising viral vector for pursuit of an AIDS vaccine," Hirsch said (see AIDS Weekly Plus, March 15, 1999).
MVA actually has been used as a smallpox vaccine and thus has an established safety record based on some 120,000 human immunizations. It uses the thymidine kinase (TK) enzyme and thus can be selectively treated with available TK inhibitors in case it gets out of hand. However, all of the MVA immune- evasion genes have been deleted, and it has a severely restricted host range. As a vaccine vector it is under investigation for use in vaccines against influenza, tumors, and malaria.
"The question isn't about safety, it's about how they work as vaccines," Hirsch said.
New MVA constructs under development at NIAID carry the SIV envelope (env), gag, and pol genes in various combinations under the control of a strong promoter sequence. Cells infected with this recombinant MVA produce virus-like particles (VLPs) that strongly resemble the wild-type virus.
The SIV vaccines were given to four groups of six macaques at months 0, 1, 4, and 7. The animals received either MVAgag- pol, MVAenv, MVAgag-pol-env, or MVA without SIV insertions.
Upon challenge with pathogenic SIV at month 8, all of the immunized animals became infected. However, the immunization with SIV antigens significantly altered the course of infection with mean challenge-virus titers lower in the treated monkeys.
"We have quite a few animals who are still doing well," Hirsch said. "Functional Gag-specific CTL are seen after the first two immunizations. Further vaccinations did not further increase this response."
Other experimental AIDS vaccines are based on avian poxviruses, most notably the Virogenetics/Pasteur-Merieux-Connaught canarypox-based ALVAC. But Hirsch said that the MLV vaccine may prove superior.
"Direct comparisons have not been made, but I think MVA is quite a bit better than ALVAC in terms of immunogenicity," she said.
The NIAID team proposed that MLV vaccines be further developed with an eye to human clinical trials.
The Hanke et al. study was supported by grants from the U.K. Medical Research Council, the U.K. Department of Health, and the International AIDS Vaccine Initiative.
The corresponding author for this study is Tomas Hanke, Institute of Molecular Medicine, University of Oxford, The John Radcliffe, Oxford, OX3 9DS, United Kingdom. Phone: (1865) 222334. Fax: (1865) 222502. Email: <thanke@molbiol.ox..ac.uk>.
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