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What If There’s No COVID Vaccine?

Although the multi-decade struggle against HIV/AIDS featured a great deal of tragedy and despair, the upshot is that medical science prevailed: what was once a death sentence is now a chronic condition. In thinking about worst-case scenarios for COVID-19, this recent experience offers both lessons and hope.

When it comes to ending the COVID-19 crisis, our experience beating back HIV/AIDS can teach us much. Above all, it was never clear during that earlier pandemic whether we could count on an eventual vaccine to be part of the solution. In our efforts to overcome today’s crisis, we would be remiss to forget this lesson.

During the early years of the HIV/AIDS crisis, I ran a laboratory at Harvard University, where we were researching the virology of the disease. Early observations showed that an HIV infection elicits an unprecedentedly strong response from both arms of the immune system – the B cells and the T cells. The body detects the threat posed by the disease, and it fights back as hard as it can, but fails. How, I wondered, can we create a vaccine that outdoes the best our bodies can do? It has now been 35 years, and we still don’t have an answer.

The quest for a COVID-19 vaccine isn’t this bleak, but nor is it particularly bright. Six decades of experience with coronaviruses – which cause the common cold as well as more serious diseases like severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) – offers reason for both optimism and caution.

The purpose of a vaccine is not to equip the body with an impenetrable shield that blocks all viruses from entry. Rather, a vaccine functions as an early warning system, alerting the body to the presence of foreign invaders and mobilizing its defenses. This rapid immune response is what clears the virus from the body before it can wreak havoc.

Although most people who develop an infection from a coronavirus (whether a feeble or potent variety) can overcome it, the exact process by which this happens remains unclear. It is a mystery, for example, why some people are able to rid themselves of an infection without any apparent help from antiviral antibodies. And even more puzzling is the fact that the same coronavirus that gives someone a cold one year can return to haunt that person the following year.

The COVID-19 virus, SARS-CoV-2, seems to fit this pattern. Several studies have already found that the protective antibodies developed by the body in its fight against SARS-CoV-2 tend to fade quickly, leaving the door open to reinfection. This finding implies that achieving so-called “herd immunity” against the coronavirus is more of a fantasy than a realistic possibility.

CRACKING THE CODE
As with HIV/AIDS, we are forced, once again, to ask whether we can do nature one better. Years of trying to develop a vaccine against SARS and MERS, and the experience so far with COVID-19 vaccines, suggests that the best we can hope for is partial, perhaps transient protection.

But even if we are unable to produce effective COVID-19 vaccines, we will not be defenseless. As in the case of HIV/AIDS, we have a two-pronged fallback strategy: deploy the tools of public persuasion to modify behavior, and develop drugs that treat and prevent infection.

This strategy reduced the toll of the HIV/AIDS pandemic dramatically. Around 1.7 million new infections still occur each year, but that is far below the rate that originally drove the number of deaths above 50 million. Whereas an HIV diagnosis used to be a near-certain death sentence, effective combinations of anti-HIV drugs have transformed the disease into a chronic condition that can be managed for a full lifespan.

The first ingredient is behavioral change. Public-health campaigns against smoking and drunk driving have taught us that modifying human behavior is difficult but entirely possible. Combined with a limited period of mandatory social distancing, efforts to encourage responsible behavior – wearing masks, avoiding large indoor gatherings – could go a long way toward controlling COVID-19.

As for the second ingredient, drug treatments, we now know that anti-virals can successfully control an epidemic, even when its causative agent is as subtle and persistent as HIV. The first success in HIV treatment came three years after the discovery of the virus, with the approval of zidovudine, a failed anti-cancer drug that had been discovered 20 years previously.

Within months of its initial success in the lab, zidovudine was proven to reduce virus levels in AIDS patients. This led to the very first remissions for patients in what had been, up to that point, a relentless progression toward death. But owing to the development of zidovudine-resistant strains of the virus in nearly all patients, relief proved short-lived.

Like HIV, cancers are persistent diseases that rapidly develop resistance to single drugs. So, to combat resistance to zidovudine, I proposed that we use a combination of anti-viral drugs against HIV, drawing on my previous experience as chair of the Division of Cancer Pharmacology at Harvard’s Dana-Farber Cancer Institute, where we developed new drug combinations to treat patients.

My laboratory started hunting for new features of the virus to target with additional anti-HIV drugs. The sequence of the HIV genome immediately revealed a wealth of opportunities, including the polymerase, ribonuclease H, integrase, protease, capsid proteins, and envelope proteins – all necessary for viral replication. Later, we discovered the tat and rev proteins, both of which are needed for viral growth, and I argued that finding drugs to inhibit any of these functions would count as a success.

Since then, more than 25 drugs have been approved by the US Food and Drug Administration for the treatment of HIV/AIDS. Most inhibit four of the seven targets. There are 11 anti-polymerase, six anti-protease, two anti-integrase, and two anti-envelope drugs available today. To date, no drugs have been approved that specifically target tat, rev, or ribonuclease H, but some are in development.

THE PREVENTION PATH
I also proposed that anti-HIV drugs be used to prevent infection following acute exposure (such as intravenous drug use or unprotected sex), and to prevent transplacental transmission. The idea was quickly adopted to protect health-care workers, and the initial resistance to using zidovudine in expectant mothers’ third trimester evaporated once we demonstrated that treatment of pregnant monkeys infected with the simian version of HIV (SIV) protected newborns from infection. Today, a combination of anti-HIV treatments for HIV-positive mothers prevents newborn infection entirely.

Finally, I suggested that anti-HIV drugs might be effective in preventing infection if attempts to develop a vaccine failed. This concept is not new. Drugs can and do prevent infection by the malaria parasite, and monoclonal antibodies protect infants from infection by respiratory syncytial virus, another virus for which no vaccine exists. Such regimens require that drugs be safe and convenient. My thoughts thus turned to the possibility that, one day, we might be able to develop a single pill that could prevent HIV infections. Three decades later, such a pill exists: Truvada, a combination of two antiviral drugs, provides robust protection from HIV infection if taken daily.

But the fact that Truvada must be taken daily tends to limit its effectiveness. As a general matter, drug compliance, even with life-saving medicines, is low. Because people tire of taking their prescribed medicines day in and day out, there is an ongoing search for longer-acting drugs. For example, with Norplant, a contraceptive medication, one treatment is effective for an entire year. Could we develop anti-HIV/AIDS drugs that do the same? If so, such drugs would serve as mini-vaccines that would need to be renewed only once a year.

Recently, two independent breakthroughs brought this dream closer to reality for HIV/AIDS. The first comes from ViiV, a collaboration between two pharmaceutical giants, GlaxoSmithKline and Pfizer, which in May reported the results of a trial to determine the effectiveness of cabotegravir, an inhibitor of the HIV integrase protein in infected men and women. The intention was to discover a long-acting version of the drug to replace daily oral Truvada, the current standard.

The study compared the effectiveness of a bimonthly injection of cabotegravir with daily doses of Truvada. Cabotegravir, when administered every two months, decreased infection more effectively than Truvada did. About 1.21% were infected in the Truvada arm of the trial, compared to 0.38% for those treated with cabotegravir. In announcing the results, Kimberly Smith, the head of research and development at ViiV, noted that, “If approved, this long-acting injectable has the potential to be a game-changer for HIV prevention by reducing the frequency of dosing from 365 days to six times per year.”

ONGOING PROGRESS
The ViiV report was soon followed by even more good news. On July 1, Gilead Sciences published a paper in Nature that is destined to become a classic in the annals of drug discovery. A tour de force of science and medicine, the study demonstrated that an entirely new class of anti-HIV drugs, the anti-capsid drug GS-6207, has the potential to protect people from infection for up to eight months with a single injection.

Gilead’s work is based on extensive prior research into the role of HIV capsid proteins. Capsid proteins provide a protective shell for viral nucleic acids, and play an active role in infection, facilitating viral entry and exit. Virus capsid proteins usually are not considered favorable targets for drugs, because one virus particle typically contains many hundreds of capsid proteins and only one or two essential enzymes. Indeed, early attempts by Gilead and others to block interactions of the capsid proteins ended in failure.

But then the Gilead team tried a different approach. Rather than searching for drug candidates that block capsid formation, they searched for drugs that accelerate capsid-capsid interaction, and it worked. Iterative chemical design allowed for the creation of compounds of ever-increasing potency. The first such compound the team described was designated GS-CA1. A modification to its structure led to the discovery of GS-6207, a potent and long-acting inhibitor of HIV replication.

The mechanism by which GS-6207 acts is both elegant and surprising. Since the discovery of HIV as the cause of AIDS in 1984, teams of scientists from around the world have sought to understand the detailed role of the capsid proteins in virus replication. Key to understanding GS-6207 is the discovery that viral entry requires close association between the capsid and host cell – especially between the capsid and a host protein known as CPSF6.

The CPSF6 protein shuttles between the cytoplasm and the nucleus of the cell. Once in the nucleus, it normally serves the purpose of processing messenger RNA. Attachment to CPSF6 facilitates entry of the HIV capsid-viral genome complex into the nucleus. CPSF6 also participates in the integration of host and viral genomes. By blocking interaction with CPSF6, GD-6207 prevents HIV from entering the nucleus and establishing a productive infection. GS-6207 also blocks late-stage infection by interfering with capsid assembly, albeit at concentrations higher than those needed to block early stages of infection.

The Gilead scientists took the investigation one step further. X-ray crystallographic studies of the capsid-GS-6207 complex show that the drug occupies the same binding site of CPSF6, which explains exactly how the drug works. In the X-ray images that show the assembled capsid, GS-6207 bridges adjacent capsid proteins—the key to how it accelerates capsid-capsid interactions. Nothing makes this scientist with a PhD in biophysics happier than understanding medically important biological phenomena based on first principles of physics and chemistry!

In fact, GS-6207 is the most potent anti-HIV drug ever discovered. It inhibits all naturally occurring HIV-1 strains tested and is active against HIV-2, as well. Moreover, Phase 1 trials with human volunteers have revealed other favorable properties: GS-6207’s clearance by the liver is very slow, its half-life is well over a month, and there were no serious adverse events to speak of.

To be sure, the downside with all HIV monotherapies is drug resistance. But the Gilead scientists were able to select viable drug-resistant viruses, and just one HIV patient in the initial trial developed low-level resistance to GS-6207. So, long-term prophylactic treatment may turn out to require a combination regimen, with a second long-acting drug such as cabotegravir.

In any case, the Nature paper’s conclusion is worth repeating in full.

“These data establish GS-6207 as a first-in-class HIV-1 capsid inhibitor with potent antiviral activity against both wild-type virus and variants that are resistant to current antiretroviral agents. The favourable safety profile, prolonged pharmacokinetic exposure and observed antiviral efficacy in humans support continued clinical development of GS-6207 as a long-acting antiretroviral agent for the treatment of infection with HIV-1, including for people living with HIV who are heavily treatment-experienced and have multidrug-resistant virus. In addition, the infrequent subcutaneous dosing renders GS-6207 an attractive candidate for the simplified prevention of the acquisition of HIV in at-risk populations – making this drug a potentially transformative tool in efforts to end the global HIV epidemic.”

HOPE YET
Frightening as the COVID-19 pandemic may be, we must not ignore the experience we have gained from our multi-decade struggle against HIV/AIDS. That experience counsels against despair, even if a vaccine fails to live up to expectations.

If the best vaccine that we can get turns out to be short-acting and only partly effective, a strategy combining behavioral change and anti-viral drugs will still offer hope – I would even say certainty – that we can treat, cure, and prevent SARS-CoV-2 infections. As we speak, monoclonal antibodies and drugs that target specific viral proteins are making their way through the clinical-trial process, and additional candidates are emerging almost weekly from laboratories around the world.

Success against HIV was made possible by continuous and sustained policy support and decades of generous funding from governments and the pharmaceutical industry for basic and applied research. As long as such commitments are maintained, we will succeed against COVID-19 as well.

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