Inactivated- or Killed-Virus HIV/AIDS Vaccines

Abstract

Inactivated or "killed" virus (KV) is a "classical" approach that has produced safe and effective human and veterinary vaccines but has received relatively little attention in the effort to develop an HIV/AIDS vaccine. Initially, KV and rgp120 subunit vaccines were the two most obvious approaches but, unfortunately, rgp120 has not been efficacious and the KV approach has been limited by a variety of scientific, technical, and sociological factors. For example, when responses to cellular antigens, present on SIV grown in human cells, proved to be largely responsible for efficacy, the KV approach was widely discounted. Similarly, when lab-adapted HIV-1 appeared to lose envelope glycoprotein during preparation (not the case for primary isolates), this was viewed as a fundamental barrier to the KV concept. Also, a preference for "safer", genetically-engineered vaccines, and emphasis on cellular immunity, have left KV low on the priority list for funding agencies and investigators. The recent suggestion that "native" trimeric gp120 displays conserved conformational neutralization epitopes, along with the failure of rgp120, and difficulties in raising strong cellular responses with DNA or vectored vaccines, has restored some interest in the KV concept. In the past 15 years, several groups have initiated pre-clinical development of KV candidates for SIV or HIV and promising, albeit limited, information has been produced. In this chapter we discuss the rationale (including pros and cons) for producing and testing killed-HIV vaccines, the prospects for success, the nature and scope of research needed to test the KV concept, what has been learned to date, and what remains undone.

HIV/AIDS epidemiology, pathogenesis, prevention, and treatment

“…Safety concerns prohibit the use of live-attenuated virus as immunogen. 199 Many different approaches with recombinant technologies have been pursued over the past two decades. Initially, efforts were focused on generating neutralising antibodies with recombinant monomeric envelope gp120 (AIDSVAX) as immunogen.…”

Short Communication:Rapid Preparation of Preventive and Therapeutic Whole-Killed Retroviral Vaccines Using the Microbicide Taurine Chloramine

“…24 An advantage of this approach is that the viral antigens are presented in a "native" conformation and composition, thereby presenting a natural immunogenic profile. However, this approach is currently not favored with HIV because of a number of overriding concerns, such as the potential presence of residual infectious virions due to incomplete inactivation, the likelihood that the harsh microbicidal agents will alter the native conformation of the virus, and the requirement for extensive and composition-altering purification steps to remove the toxic microbicide.…”

“…Nevertheless, efforts continue to be made to find agents that are capable of completely inactivating whole viruses, but are at the same time mild enough not to appreciably disturb the native conformation of the viral envelope. [24][25][26][27][28] The highly effective HIV-killing properties of T-NCl, the nontoxic properties of this natural compound, and its selectivity for viral cysteines all suggested that this agent may prove successful in the preparation of effective and safe whole-killed HIV vaccines. The present study therefore examined this possibility in vivo with the murine AIDS (MAIDS) model.…”

“…41,42 The ability of T-NCl to facilitate the production of wholekilled retroviral vaccines is particularly noteworthy, given the high degree of difficulty associated with the preparation of such vaccines. 24 One key obstacle to the production of such vaccines is the requirement for harsh chemical agents to inactivate the virus. These agents frequently alter the native conformation of the virus.…”

“…Since the current "modern" efforts at vaccine preparation (e.g., recombinant proteins, synthetic peptides) are faltering, it may be time to seriously reexamine the possibility of returning to the more "classical" approach of whole-killed vaccines. 24 The clear advantage of whole-killed virus vaccines, namely, the presentation of intact immunogenic native envelope glycoproteins, has been recognized for a long time. Moreover, the whole-killed viral vaccine approach has been singularly successful to date in the preparation of safe and effective retroviral vaccines for both human and animal use.…”