The Failure of AIDS Vaccine Efficacy Trials: Where to Go from Here

ABSTRACT

The seven AIDS vaccine efficacy trials have yielded extremely disappointing results at great expense. Greater stringency is needed for government support of AIDS vaccine efficacy trials.

TEXT

There are good reasons for believing that development of an effective, preventive vaccine against HIV/AIDS is going to be a very difficult task. There is enormous strain variability among human immunodeficiency virus (HIV) strains even in a narrowly defined geographic region: much more than influenza virus and the COVID coronavirus. Antibodies mounted against one strain may neutralize that one strain to one extent or another but typically do not neutralize the vast majority of other strains circulating in the population. HIV is highly tolerant to change, and variant viruses quickly emerge in a recently infected individual that escape the neutralizing activity to the original infecting strain (1). Once an HIV infection is initiated, virus replication is continuous and unrelenting despite apparently strong immune responses to the virus. Despite these apparently strong immune responses, natural HIV infection does not prevent superinfection by other strains of virus circulating in the population (2). What are we going to put into a vaccine to protect against this beast?

These predicted difficulties have been borne out by the seven vaccine efficacy trials performed to date (Table 1). The first five trials unambiguously resulted in no protection against HIV acquisition and no lowering of viral load. In fact, the STEP and the Phambili trials resulted in a statistically significant enhancement in the numbers of HIV infections in the vaccine group (3). The sixth trial, the RV144 trial, initially reported an early, transient, marginal decrease in the acquisition of HIV infection among those in the vaccine group (4). However, there were oddities in the data from that trial (5) and a subsequent follow-up publication on the statistics reported that there was less than a 79% chance that the protection reported for that trial was real (6). A follow-up trial (HVTN702) was performed “to confirm and extend the results of the RV144 trial.” In 2021, results from that trial were released. HVTN702 was halted because of futility: no protection against HIV acquisition and no lowering of viral loads (7).

TABLE 1.

Vaccine efficacy trials performed to date and their outcomes

Trial	Vaccine	Outcome
Vax-Gen (a)	gp120 (b) in adjuvant	No protection
Vax-Gen (b)	gp120 (a+e) in adjuvant	No protection
STEP (Merck)	Gag/Pol/Nef recAd5	Enhancement
Phambili	Gag/Pol/Nef recAd5	Enhancement
HVTN505	Gag/Pol/Nef/Env DNA+Ad	No protection
Thai RV144	Gag/Env recPox + gp120	Possibility of some protection?
HVTN 702	Essentially similar to RV144	No protection

These results should not be surprising. The vaccines failed to elicit antibodies capable of neutralizing a broad range of HIV field strains and they failed to elicit immune responses that persisted in an up/on/active fashion. Administration of Env protein or use of a nonpersisting vector platform elicits anti-Env antibodies with a short half-life. In contrast, use of a persisting herpesvirus vector or live attenuated simian immunodeficiency virus (SIV) yields moderate-high levels of anti-Env antibodies that persist at stable levels for years, decades, life (8, 9). Similarly, the nonpersisting approaches favor generation of central memory T cells while the persisting approaches favor effector memory T cells that are poised for immediate antiviral activity.

In addition to the efficacy trials cited above, results of the Mosaico and of the Imbokodo efficacy trials have been recently announced but not yet published. Both trials used an Adenovirus 26 recombinant expressing a mosaic gp140 envelope protein. The Mosaico trial was held in North America, South America, and Europe and the Imbokodo trial was held in sub-Saharan Africa. Both trials have been halted based on futility: no protection against HIV acquisition and no lowering of viral loads in those infected (https://www.avac.org/blog/mosaico-hiv-vaccine-study-stopped-early-non-efficacy).

Ongoing research is slowly making progress in overcoming both the neutralization and the immune persistence deficiencies noted above. Rare monoclonal antibodies have been discovered that can neutralize a broad range of HIV isolates. Ways are being investigated to achieve lifelong delivery of such antibodies from a single intramuscular administration of adeno-associated virus (AAV) vector. Examples of continuous delivery of monoclonal antibody at concentrations over 100 μg/mL for over 5 years from a single day administration to monkeys have been documented (10, 11).

Herpesviruses are a family of lifelong persisting viruses. The vaccine for chicken pox in children is a live attenuated herpesvirus vaccine that has been put into millions of people. A recent Perspectives article by prominent authors in the Nature Journal npj Vaccines has advocated for pursuit of a vaccine for the Kaposi sarcoma herpesvirus (KSHV), the gamma-2 herpesvirus of humans (12). Several groups are investigating the potential of recombinant herpesviruses for elicitation of lifelong immune responses to AIDS virus. A recombinant gamma-2 herpesvirus of rhesus monkeys has been described with a near-full-length, replication-incompetent SIV genome insert that expresses all nine SIV gene products, elicits immune responses to all nine SIV gene products, and elicits long-term constant expression of anti-SIVenv antibodies. This recombinant has provided impressive protection against acquisition of infection following intravenous challenge with SIVmac239, a strain notably difficult to protect against (8). A recombinant CMV vector has been described that elicits unusual cellular immune responses and can strongly control SIVmac239 replication in approximately 50% of challenged monkeys. This CMV recombinant does not contain an SIV envelope gene or elicit anti-SIVenv antibodies and has not protected against the acquisition of infection (13). Neither approach has yet succeeded in achieving broadly neutralizing activity.

Both the recombinant herpesvirus and AAV-antibody areas of research need to be significantly ramped up. A pressing need in efforts to develop a vaccine for HIV using recombinant herpesvirus is to figure out a way to take advantage of the lifelong recurring antigen expression to elicit antibodies with potent broadly neutralizing activity. The most pressing problem with recombinant AAV expression of anti-HIV monoclonal antibodies is antidrug antibodies (ADA), an antibody response to the AAV-delivered antibody that negates its continuing presence. This is the most common outcome both in monkeys and phase 1 human trials to date (14, 15). Other modern, state-of-the-art approaches are also deserving of ramped up attention. These include but are not limited to: mRNA methods à la COVID; targeting of germ line precursors (16); and nanoparticle targeting of B cell follicles (17). But these approaches will need to struggle to one extent or another with the same issues of persistence and elicitation of broadly neutralizing activity.

The most recent HVTN702 trial has been quoted as costing $104 million (18). The costs of the other published trials are likely to have been similar. Most of the costs of the published efficacy trials have been borne by the United States government, more specifically the National Institutes of Health and the U.S. military. The Mosaico and Imbokodo trials did receive significant financial backing from the Janssen Pharmaceutical Companies. In the free enterprise systems operating in the United States. and much of Europe, the cost of product development is generally borne by companies. They take the risk, and they get the profit if it works. The role of the National Institutes of Health should be to fund the basic and developmental research that will make a vaccine possible. More specifically, elicitation of broadly neutralizing activity and persistence of immune responses not simple immunologic memory. Others have also expressed concerns over the decisions to move forward with these vaccine trials (19, 20).

The time has come to establish criteria for extensive government funding of vaccine efficacy trials against HIV. The vaccine candidate must: (i) elicit antibody responses capable of neutralizing most HIV strains circulating in the population; (ii) induce immune responses that are up/on/active for life, not just immunologic memory; and (iii) yield highly impressive protection against both homologous and heterologous virus challenge in valid animal models for AIDS.

The views expressed in this article do not necessarily reflect the views of the journal or of ASM.