As surprising as it sounds, one of history’s best proven vaccine methods has never been seriously tested for HIV, even though it potentially could have interrupted the AIDS pandemic long ago.

A killed virus vaccine modeled after classical vaccines for polio, influenza, and other diseases still may be able to interrupt the AIDS pandemic long before anyone can invent a better way — possibly decades sooner.

Yes, killed-virus vaccine methods were used to stop the U.S. polio epidemic in the 1950s, and have been used ever since for polio and other viral diseases including rabies, flu, and hepatitis B. Hundreds of millions of doses of killed-virus vaccines have been safely administered to men, women and children in the U.S. and elsewhere.

No. Little attention and almost no research funding has been directed to killed-HIV vaccines, despite the fact that killed-virus vaccines have delivered clear clinical benefit for several animal diseases caused by retrovirus related to HIV. Scientific review panels have concluded that work to date has not been sufficient to rule in or to rule out the killed-virus vaccine approach for HIV/AIDS.

No, this is not a criticism of anything that has been done by NIH, IAVI, other foundations, or anyone else. The problem is that the historically-successful killed-virus vaccine approach has slipped through the cracks and remains untested for HIV to this day. See more detail below.

Essentially all funding for HIV vaccine research has gone to basic research intended to enhance understanding of the underlying biology, or to novel genetically-engineered vaccine methods that it is hoped may work for HIV. Such research is important and may lead to a better vaccine method one day. But there is no telling how soon. Success may be decades off.

Given the global devastation that HIV/AIDS has caused for over 30 years, it is difficult to grasp how one of the best-established vaccine methods has been omitted from the entire research agenda. The short answer is that killed-virus has simply slipped through the cracks between the various entities engaged in HIV vaccine research.

Biotech and pharmaceutical companies see no profit potential in a vaccine based on old-fashioned public-domain technology. Meanwhile academic scientists can get no support or funding for product development using “old” science as opposed to seeking new scientific understanding. And practical vaccinologists have never obtained serious funding for killed-virus work from any of the traditional sources.

So while it never has been anyone’s explicit policy to entirely omit one of the most historically-successful vaccine methods from the mix for HIV/AIDS, that effectively has been the outcome.

Yes. Contemporary industrial technology and laboratory methods are able to ensure that every last infectious virus particle is eliminated during the manufacture of killed-HIV vaccines. Killed-virus vaccines have been used safely for decades for viral diseases including rabies— a pathogen just as lethal as HIV but one that claims its victims far more quickly.

Best case, two years for preparatory laboratory research. Another three to four years for clinical trials. If those trials succeed, three to four more years to manufacture and deploy vaccine globally. All told, ten years or less from start to finish.

No. The truth is, scientists do not yet understand enough about HIV biology to make reliable predictions about just how well any HIV vaccine approach will work. Many scientists see little reason to hope that novel methods will produce an effective vaccine any time soon.

Yes. Numerous members of the science and public health communities have written letters in support of the killed-virus approach.

On the other hand, the majority of researchers anticipate bigger rewards from use of novel modern genetic engineering methods. In the long run, they may be right. But, there is no telling how long it will take to produce an effective vaccine with still-unproven methods, and we need a vaccine now.

In fact, one Nobel laureate biologist said this as early as 1994:

“I can see no earthly reason why the [killed-virus vaccine] strategy should not be tried. After all, it has produced many effective vaccines in the past, including one against a retrovirus (FeLV, now in commercial use). And given the woeful state of understanding of the immune response against HIV, I would distrust any criticisms based on theoretical grounds.”

As Dr. Marcus Conant says in the accompanying video, we will not know whether or not it will work until we test it. But there is ample reason for hope. And we need not speculate! We know exactly how to test it, and within a few years we can know the answer for sure.

We arguably have proof of concept from animal retrovirus models, viz. horse (EIAV), goat (CAEV), cats (FIV and FeLV); and macaques (SIV). However every review panel that has reviewed this subject has concluded that prior experiments are insufficient to prove or to disprove the killed-virus concept. The only way to answer the question authoritatively is to undertake a systematic, comprehensive vaccine development effort.

No. Killed-virus vaccines need not employ “whole” virus. Many killed-virus vaccines, like vaccines currently used for flu, use disrupted (“split”) virus particles.

We have no way to know how straightforward or difficult it will be until the concept is tested in humans. But several effective killed animal retrovirus vaccines have been developed in the past using the killed-virus paradigm, so we have reason to be optimistic.

The HIV variability/mutability issue is in no sense special to killed-virus vaccines; every vaccine paradigm must confront this issue with HIV. However killed-virus vaccines do offer useful strategies to address viral variability. “Multivalent” killed-virus vaccines such as the flu vaccine and poliovirus vaccine have proven effective against multiple virus strains. In principle, chemical or biomedical modifications can also be employed to blunt immunogenicity of variable viral epitopes. Either of those strategies arguably can be investigated much more efficiently and more promptly using killed virus than using any high-tech approach based on genetically-engineered constructs. Finally, even if we never get a globally-effective vaccine, effective vaccines targeting circulating strains in specific locales could alleviate suffering and save countless lives.

This concern arises because the vaccines tested to date, if they elicit neutralizing antibodies at all, typically produce quite “narrow” responses, i.e., antibodies that do not neutralize strains different than the immunizing strain. At this point, we simply do not know enough about the underlying biology to make meaningful predictions about how well any approach might work, why it might, or why it might not. But if we could make a vaccine that produced clinically useful endpoints, even if the protection was “narrow” in the sense described above, arguably this would enable us to define correlates of narrow protection, and it might be a useful step on the way to a more broadly-protective vaccine. Bottom line, were we to exclude study of vaccines that might not work, or that might not yield broad protection, we would have nothing at all to investigate.

In the context of HIV/AIDS, this idea sounds better than it actually is. A vaccine concept that works in one species may or may not work in another. So far, we do not have any animal model that reliably predicts outcomes in humans. Furthermore, to develop a retrovirus vaccine that works in animals would take just as much time, money and effort as to develop a vaccine that works in humans. Bottom-line, other than information on acute toxicology, there is little to be gained from animal testing of killed-virus or any other retrovirus vaccine. It likely would be much more informative to compare and contrast a variety of candidate killed-HIV vaccine formulations in small human trials.

It would certainly be a wonderful stroke of luck if any of the specific vaccine formulations currently known to be in development were to prove effective, including those using elements of killed-virus methodology. But experienced researchers will be aware that vaccination outcomes can be influenced by a sizable list of vaccine input variables. We typically have needed a large number of guesses, considerable empirical screening, multiple iterative trials, and numerous small incremental improvements before we hit upon vaccine formulations that worked. Thus we think a successful classical vaccine is most likely to emerge through a comprehensive product development effort, rather than a single vaccine formulation. Barring a stroke of massive good luck, considerable empirical trial and error experimentation is apt to remain an essential element of any successful AIDS vaccine development effort.

No viral vaccine — using any method — has ever been able to completely and routinely prevent infection. But classical killed-virus vaccines have demonstrated ability to inhibit virus growth, defer disease, attenuate symptoms, and reduce the probability of transmission. All of these would be clinically-useful outcomes for HIV/AIDS.