VACCINE PROTECTION BY A TRIPLE DELETION MUTANT OF SIMIAN IMMUNODEFICIENCY VIRUS

Twelve rhesus monkeys were vaccinated with SIVmac316 Delta nef (lackin g nef sequences), and 12 were vaccinated with SIVmac239 Delta 3 (lacki ng nef, vpr, and upstream sequences in U3). SIVmac316 and SIVmac239 di ffer by only eight amino acids in the envelope; these changes render S IVmac316 highly competent for replication in macrophages, Seventeen of the animals developed persistent infections with the vaccine viruses, Seven of the 24 vaccinated animals, however, developed infections tha t were apparently transient in nature, Six of these seven yielded viru s from peripheral blood when tested at weeks 2 and/or 3, three of the seven had transient antibody responses, but none of the seven had pers isting antibody responses, The 24 monkeys were challenged in groups of four with 10 rhesus monkey infectious doses of wild-type, pathogenic SIVmac251 at weeks 8, 20, and 79 following receipt of vaccine. None of the seven with apparently transient infections with vaccine virus wer e protected upon subsequent challenge, Analysis of cell-associated vir al loads, CD4(+) cell counts, and viral gene sequences present in peri pheral blood in the remainder of the monkeys following challenge allow ed a number of conclusions, (i) There was a trend toward increased pro tection with length of time of vaccination, (ii) Solid vaccine protect ion was achieved by 79 weeks with the highly attenuated SIV239 Delta 3 . (iii) Solid long-term protection was achieved in at least two animal s in the absence of complete sterilizing immunity. (iv) Genetic backbo ne appeared to influence protective capacity; animals vaccinated with SIV239 Delta 3 were better protected than animals receiving SIV316 Del ta nef. This better protection correlated with increased levels of the replicating vaccine strain, (v) The titer of virus-neutralizing activ ity in serum on the day of challenge correlated with protection when m easured against a primary stock of SIVmac251 but not when measured aga inst a laboratory-passaged stock, The level of binding antibodies to w hole virus by enzyme-linked immunosorbent assay also correlated with p rotection.