The vaccine alternatives for people with compromised immune systems

Drug makers are increasingly turning to monoclonal antibodies to protect the millions of people who may not be able to use vaccines. But questions swirl about their cost and long-term viability.

As the COVID-19 vaccine rollout gathers pace, a population is at risk of being left behind: the millions of people around the globe who lack fully functional immune systems.

While the exact number of the immunocompromised worldwide is unknown, estimates suggest that about 10 million live in the U.S. alone, or around 3 percent of the national population. The number encompasses a diverse range of vulnerabilities, including rare genetic immune deficiencies, chronic illnesses that impair the immune system such as rheumatoid arthritis, and cancer and organ-transplant patients who must take immune-suppressing medications.

For them, vaccines may not be as effective, because they are less capable of making their own antibodies to neutralize the SARS-CoV-2 virus. Instead, pharmaceutical companies around the world are racing to develop alternative treatments that bypass the immune system altogether.

The most common option is called monoclonal antibody treatments. These artificially generated antibodies mimic the body’s natural immune response by binding to key sites on the virus’ spike protein, preventing it entering cells and reproducing. Companies including AstraZeneca, Regeneron, and Eli Lilly are currently testing whether monoclonal antibodies can protect immunocompromised people from SARS-CoV-2.

“You often find that patients who have had bone marrow transplants end up getting terrible flu and other infections, which they can’t clear without additional help,” says Nicky Longley, an infectious diseases consultant at University College London Hospitals. “It was these heavily immune-suppressed populations who did very badly during the first wave of COVID-19.”

In addition, preventing immunocompromised people from getting infected will be a key part of keeping the disease in check in the long run, says Andrew Ustianowski, an infectious disease specialist at the U.K.’s National Institute for Health Research.

“If we want to control this virus and get back into normal life, then being able to protect everybody, so we don’t have ongoing transmission in subgroups of the population, is important,” he says.

But while many scientists are excited about the potential of monoclonal antibodies to address gaps in the world’s vaccination programs, questions remain. The coming months will tell us whether these treatments are sufficiently cost-effective to be used on a large scale, if they can really provide adequate protection for months at a time, and whether using monoclonal antibodies may inadvertently do more harm than good.

A potential ‘game changer’

In the past, the only alternative means of protecting immunocompromised people during viral outbreaks was a product called intravenous immunoglobulin, or IVIG. Taken from the blood plasma of healthy donors, infusions of IVIG are one way of supplying patients with natural antibodies against a broad range of infections most people are commonly exposed to.

But supplies are limited, and IVIG is expensive, with a single patient’s cost sometimes reaching up to $30,000 a year. It also provides protection for only three weeks at a time, as the antibody concentrations in the product slowly wane, and it isn’t guaranteed to work against any specific virus.

“If you could get them a more targeted form of passive immunization which is made synthetically, it could be a real game changer,” says Longley.

However, creating monoclonal antibodies is also a painstaking process. It involves first extracting a broad range of antibodies from the blood of recovering patients, testing them in animals to identify which are best at neutralizing the virus, cloning the chosen ones in the lab, and then growing them in sufficient quantities in gigantic steel bioreactors.

Because of the time it takes to make a finished product, monoclonal antibodies were long considered impractical against viruses. Over the past decade, they have been most commonly used as treatments for cancer and autoimmune diseases.

“Viruses mutate rapidly, so scientists might well find the perfect site, begin production of the perfect monoclonal antibody, and then all of a sudden the virus mutates so the antibody doesn’t bind as well, or worse, doesn’t bind at all,” says Rodney Rohde, professor of clinical laboratory science at Texas State University.

But various research programs have driven a number of technological advances in recent years. Antibodies can now be isolated from convalescent patients in less than a month, while virologists have got progressively better both at identifying sites in the viral genome that are less likely to mutate. Five years ago, the quickest time frame for creating monoclonal antibodies was 18 months. Today, it’s about 10 months.

Even more crucial, scientists have tweaked the underlying structure of monoclonal antibodies, making it harder for the body to remove them from the bloodstream—meaning they can potentially last for months at a time rather than weeks.

These developments had initiated renewed interest in monoclonal antibodies as virus fighters even before the COVID-19 pandemic. A study published in December 2019 found that such treatments reduced mortality during an Ebola outbreak in the Democratic Republic of the Congo by 15 percent. And that autumn, the National Institute of Allergy and Infectious Diseases (NIAD) funded a research program to assess the viability of identifying monoclonal antibodies for use against seasonal influenza.

Now, Ustianowski is leading a global clinical trial called PROVENT, in conjunction with AstraZeneca, that’s attempting to find monoclonal antibodies that will work against SARS-CoV-2. In the PROVENT trial, 5,000 people around the world with various immune deficiencies will receive a dose of either a monoclonal antibody-based cocktail or a placebo. They’ll be followed over the course of a year to see whether the treatment prevents them getting COVID-19, and how long protection lasts.

If PROVENT is successful, Longley suggests that the treatment could also be used to protect people who produced too few natural antibodies in response to the vaccine, such as elderly individuals whose immune systems are not as active. This would mean that even though they have had the vaccine, they are not protected. “Vaccines take a bit of time to build immunity in the body, but injecting monoclonal antibodies should work immediately, so it could work as a preventative measure,” she says.

Both Eli Lilly and Regeneron are already looking at whether these antibodies can offer protection to nursing home residents in areas where the vaccine rollout has been delayed. Last week, Eli Lilly released data from a phase three trial which showed that its monoclonal antibody treatment bamlanivimab reduced the risk of contracting COVID-19 by up to 80 percent in care facilities.

In the longer term, with COVID-19 widely expected to develop into an endemic disease, Ustianowski predicts that monoclonal antibodies could be used as periodic boosters every six months to a year to protect vulnerable immunocompromised people even after herd immunity has been achieved in the general population.

“Coronavirus is not going to disappear from the Earth over the next few years,” he says. “For those at ongoing risk, I could imagine them receiving these periodic injections.”

Fears of an access gap

One of the major hurdles for monoclonal antibodies has always been the staggering costs. While seven of the top 10 best-selling drugs of 2019 were monoclonal antibodies for cancer and autoimmune diseases, one study found the average annual price per patient worked out to be $96,731. Access has therefore been restricted to only the wealthiest nations. Currently, 80 percent of global sales of licensed therapeutic antibodies are in the U.S., Europe, and Canada.

Pharmaceutical companies making monoclonal antibodies for COVID-19 insist that the price tag per dose will not be in the tens of thousands.

“We’re not ever going to be talking about a price for these drugs that’s of the order of $100,000,” says Alexandra Bowie, a spokesperson for Regeneron. “If you look at what we’ve done so far, the price per dose for the contracts we’ve signed with the U.S. government is more on the order of $2,000.”

However, $2,000 is still significantly more expensive than vaccinations, and the price may prove unaffordable in many parts of the world. By comparison, the Pfizer-BioNTech jab costs $20 per dose, and the AstraZeneca vaccine comes in at just $4 per dose. On balance, though, Ustianowski argues that it’s better to have the drugs available for the smaller portion of the population that really needs them.

“This isn’t for everybody; it’s just for those that can’t have the cheaper and more cost-effective vaccines,” Ustianowski says. “If you’re talking about a subset of individuals, then it’s easier to encompass that cost.”

Steps are already being taken to address the potential access gap. Bowie says that the U.S. government has so far committed to making 1.5 million doses ordered from Regeneron free for patients, regardless of whether they have health insurance. Currently this batch is being used as treatments for non-hospitalized patients with mild to moderate cases of COVID-19, though future supplies could be used as passive immunizations pending regulatory approval. In addition, she says a donation strategy will be put in place specifically for lower- and middle-income countries, in conjunction with their manufacturing partner, Roche.

Jens Lundgren, an infectious disease physician at the University of Copenhagen, also expects pharmaceutical companies will strike deals with generic drug manufacturers in lower-income nations.

“The actual production price once you have the antibody clones developed is very minimal,” he says. “This is why you can already see generic manufacturers in Asia producing monoclonal antibodies for some autoimmune diseases and selling them at a very low price per dose.”

Safety first

But cost is only one of the concerns surrounding monoclonal antibodies. There are safety issues to consider, which will be monitored closely in both the PROVENT trial and other clinical trials.

One of these is a troubling phenomenon called antibody-dependent enhancement, which was observed by scientists trying to create vaccines against dengue fever. Receptors on the tail region of antibodies normally bind to immune cells, allowing antibodies to activate the immune system. In some cases, though, it seems these receptors can accidentally attach to viruses too, allowing the pathogens to access cells rather than stopping them. Monoclonal antibody manufacturers are now taking steps to minimize that likelihood, such as engineering receptors with mutations that limit the risk of virus binding.

Another major issue is whether monoclonal antibodies could quickly become obsolete as new variants of SARS-CoV-2 emerge, something which is already proving to be a challenge. Recent studies conducted in the U.S., South Africa, and China suggest that Eli Lilly and GSK’s products, which each consist of a single monoclonal antibody, may not work against one or more of the three major variants of SARS-CoV-2. These papers were released on the bioRxiv preprint server and are not yet peer reviewed.

Regeneron's product consists of a cocktail of two monoclonal antibodies, and the data suggest it is still effective against the variants. Eli Lilly and GSK are testing whether combining their products into an antibody cocktail can improve efficacy. There is no data yet for how AstraZeneca’s monoclonal antibody product fares against the variants.

Another theory suggests that using these products as emergency treatments for hospitalized patients could encourage viral evolution. A recent lab study found that the virus is indeed capable of deliberately mutating to evade multiple antibodies found in convalescent plasma. If monoclonal antibodies derived from this plasma do not immediately inactivate the virus, they may encourage it to mutate further, creating new variants.

At the same time, many scientists involved in monoclonal antibody research believe that greater use of them as passive immunizations in vulnerable populations could actually help stop new variants from appearing.

“For most of 2020, the majority of the population was immunologically naïve to this virus, and thus the virus was freely circulating among vulnerable individuals, including the immunocompromised individuals,” says Ali Ellebedy, assistant professor of pathology and immunology at Washington University School of Medicine. In the immunocompromised, the virus can keep replicating—and thus mutating—in the same person for weeks, providing what Ellebedy calls the “perfect platform” for new variants to emerge. In theory, protecting more of these vulnerable people can thus limit the virus’s chances of spawning new variants.

For the scientists leading the PROVENT trial, much depends on the coming months and whether monoclonal antibodies can be shown to provide long-lasting protection in vulnerable populations. If so, they feel this will open doors for monoclonal antibodies protecting more immunocompromised patients as part of standard medical care.

“If effective, I could see these immunizations being used in some cancer patients, for example those who are being treated for acute leukeumias,” says Longley. “They can’t have vaccines, and you’re worried about them being exposed during a flu or a measles outbreak. This could keep them safe until they have their curative treatment.”

Editor's Note: This story has been updated with the latest amount of Regeneron's monoclonal antibody product available in the U.S., and to correct how well their product has been shown to work against known virus variants. Additionally, the story has been updated to better reflect how well vaccines work for the immunocompromised.

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