The Toughest Nut to Crack: Will We Ever Have a Preventive and Effective HIV-1 Vaccine?

See page 2021

In this issue of Molecular Therapy, Negri et al. report that a simian immunodeficiency virus (SIV)-based lentiviral vector encoding the human immunodeficiency virus type 1 (HIV-1) envelope protein (Env) under the control of an internal cytomegalovirus promoter elicited antibody and T-cell responses in rhesus macaques.¹ The antibodies elicited can block the binding of HIV-1 Env to its CD4 target molecule and show antibody-dependent cell-mediated cytotoxicity (ADCC) in all animals tested after vaccine boosting. The lentiviral vector used was integrase-defective, an important safety measure that should minimize integration in the host genome. The expression of the transgene was mediated by episomal plasmidlike forms of the recombinant vector. The main importance of this article is that the authors have devised a vaccination tool that leads to the production of antibodies that lasts longer than that achieved in other reported SIV/HIV vaccination studies. These responses last for at least one year and can be significantly augmented by a booster vaccination. Moreover, these anti-Env antibodies are of particular interest because some of their properties have been associated with protection against HIV-1, i.e., (i) they have ADCC activity; (ii) they are directed against the variable region 2 (V2) of Env; (iii) they are present in mucosal secretions; and (iv) they bind Env from different HIV-1 clades and block the CD4-binding site of Env.

To put the findings of Negri et al. into perspective, one needs to consider the long, arduous, and largely frustrating history of HIV-1 vaccine development. The AIDS epidemic is still progressing through the world, but a much sought-after preventive HIV-1 vaccine remains elusive. Recently Bob Gallo summarized the problems in developing an effective HIV vaccine and recalled Albert Sabin opining some 30 years ago that an HIV vaccine would not be possible.² The only HIV-1 vaccine trial showing any efficacy in humans, the ALVAC-prime AIDSVAX-boost RV144 trial, only reduced the infection rate by 31.2%.³ The protection afforded in this trial was correlated with the induction of antibodies directed against HIV-1 Env, which were capable of mediating ADCC.^4,5 However, the action of these antibodies was short-lived, and protection waned rapidly. This seems to be a general feature of vaccination efforts against HIV-1 and SIV.² Another problem with SIV and HIV vaccines is the stimulation of CD4⁺ T-lymphocyte help for antibody generation, which also expands the pool of activated cells that are highly susceptible to HIV or SIV infection.⁶ This problem of “excessive” CD4⁺ T-cell stimulation was most probably the main reason that, in two HIV-1 vaccination studies employing recombinant adenovirus vectors, the infection rate actually increased in vaccinated individuals.⁷

Negri et al. most probably succeeded in increasing the duration of the antibody response, because they used a nonintegrating lentiviral construct delivered by intramuscular injection. This strategy allowed for a longer transgene expression (in the absence of cell division),⁸ stimulating antibody production. In a study comparing immunization of rhesus macaques with env DNA and/or Env protein, the durability of humoral antibody response was mainly influenced positively by the DNA administered by electroporation.⁹

The road is still long from the present publication to an effective, fully protective HIV-1 vaccine, which may remain elusive in the end. First, the authors will have to demonstrate some protection against viral challenge in monkeys. Real-life vaccination will probably need to include at least two boosters administered within a timespan shorter than one year because only after one booster did all six monkeys studied develop the critical antibodies with ADCC activity, and even this only lasted up to 13 weeks in one of the six animals. Concomitantly with the viral challenge in vaccinated animals, the durability of the immune responses will have to be checked, and lentiviral integration and recombination events, however unlikely, will have to be assessed. It is also to be hoped that the CD4⁺ T-cell response elicited by the lentiviral vaccine (far more than a potentially protective CD8⁺ cytotoxic T-cell response¹⁰) will not lead to a cell population that can readily be infected by the challenging virus, which then may be ineradicable. Subsequently, broad protection against different strains will have to be achieved, most likely by immunogen design strategies that induce broadly neutralizing antibodies.¹¹ Finally, if there is sufficient protection in the animal models, vaccination trials in humans will have to be planned following tailoring of the lentiviral construct and its insert(s).

The field of HIV-1 vaccination has become less bleak though, first by the observation of the actual (but modest) protection against HIV-1 infection in the ALVAC-prime AIDSVAX-boost RV144 trial³ and second by the present and other studies showing that it is possible to improve the duration and the breadth of critical antibody responses.^{1, 6, 9, 11}