What can SA do to prepare for snake antivenom shortages?

The most widely used snake antivenom product in South Africa – called SAIMR polyvalent – may still be effective long after it has expired, according to a recent study. The drug is made by the South African Vaccine Producers (SAVP), a state-run company, which last year struggled to produce enough of the product to meet demand.

The result was a nationwide shortage of the life-saving medicine, which plagued the country for several months.

The problem was compounded by the fact that antivenoms are difficult to stock. Carine Marks, director of the Tygerberg Poison Information Centre, says that the South African antivenoms “don’t have a long shelf-life, and they’re expensive”. As such, “hospital pharmacies don’t want to unnecessarily stock [too much] antivenom”, since they may end up throwing it away, she says.

However in the new study, published in the British Medical Journal, researchers argue that health facilities in South Africa should consider holding on to expired stocks of SAIMR polyvalent antivenom. Alternatively, they suggested companies and regulators look into extending the drug’s three year shelf-life.

The reason? SAIMR polyvalent antivenom, which was well past its sell-by date, remained effective at treating mice that had been exposed to puff adder venom. The researchers tested eight ampoules of the drug – each of which had expired sometime between 1991 and 2017 – yet they found no drop-off in efficacy among older batches.

The contents of the two oldest vials (which expired in 1991 and 1993 respectively) were cloudy, which means that proteins in the drug had likely clumped together, increasing the risk of side-effects when administered. However, the other six remained clear (the oldest of which expired in 1997) and several laboratory tests found that they had not significantly deteriorated.

Ultimately, since the research was done in a laboratory, not on real-life patients, there’s no certainty the results will hold in humans. Mzi Gcukumana, the spokesperson for the National Health Laboratory Service, a state entity that owns the SAVP, told Spotlight that once antivenom has “gone beyond its permitted shelf life, the [National Health Laboratory Service] cannot guarantee its quality or efficacy”.

Nevertheless, the World Health Organization does state that “recently expired antivenoms may be used if there is no alternative”. According to Marks, that’s in line with the advice of the Western Cape Poison Information Centre (provided the doses aren’t cloudy).

Dr Stuart Ainsworth, a scientist at the University of Liverpool, who co-authored the recent study, says “it’s been known for decades that expired antivenom may still be clinically efficacious if you keep them in decent conditions [and] store them properly”.

Though he notes that “this is easier said than done in some areas in Sub-Saharan Africa”.

Should South Africa face another acute shortage of the SAVP-made antivenoms, health workers will need to be given clear guidance about whether they can use expired stocks – something which does not appear to be current standard practice.

Dr Andy Gray, a senior lecturer in pharmacology at the University of Kwazulu-Natal, told Spotlight that for a pharmacist to issue or dispense expired medicine would “be a real exception to normal practice”. Another senior pharmacist, Dr Sham Moodley, suggested the same.

CAN WE TRUST THE SAVP'S PRODUCTS?

At present, the SAVP makes three antivenom products. The SAIMR polyvalent treatment is used to counteract bites from ten prominent snake species across the country, such as the Puff Adder, Rinkhals and Cape Cobra. A second product is used to treat bites from the Boomslang specifically, and a third is aimed at the saw-scaled viper (which is usually only found north of South Africa’s border).

How well do these products work?

A 2019 review found that while the SAVP’s SAIMR polyvalent product is “one of the most clinically-trusted antivenoms in sub-Saharan Africa… there is paradoxically very little published material providing robust evidence of its efficacy”. It came to similar conclusions about the Boomslang product.

However, according to Ainsworth, clinical trials on antivenom are generally difficult to conduct, regardless of the product. “There have been some done,” he says, but they can be ethically tricky: “you can’t give a placebo to a person who’s just been bitten by a snake” (making it difficult to compare the effects of antivenom to a control group).

One of the very few randomised clinical trials that has been conducted focused on patients that had been bitten by a venomous, but non-lethal, snake. Since the bite couldn’t kill them, researchers considered it ok to give some patients a placebo to compare with those who got antivenom (the findings of this very small study showed the drug was effective). Clearly, this kind of research would not be ethical in the case of a Cape Cobra or Rinkhals bite, however, making it harder to trial SAIMR polyvalent antivenom.

Nonetheless, preclinical studies (i.e. research done on mice and in petri dishes) have found the SAIMR polyvalent product to be highly effective against several snake species. Dose for dose, the drug was “considerably more effective” against the Egyptian Cobra, Black Mamba and Puff Adder than four other major antivenom products, including respected European brands.

Researchers and health workers who spoke to Spotlight also said they generally find the South African made antivenoms to be very effective.

THE PROBLEMS: SIDE-EFFECTS, HIGH PRICE TAGS AND LOOMING SHORTAGES

Yet while most have faith in their efficacy, the SAVP products are well known to come with a host of problems.

Regardless of the brand, all antivenoms have the capacity to produce side-effects, including anaphylactic shock, which is when a person’s blood pressure drops and they struggle to breathe (something which is treated with adrenaline).

However, a literature review found that the SAIMR polyvalent product is particularly prone to causing these side-effects. Indeed, according to Ainsworth, “the South African products, while apparently very effective at treating snake envenoming, are notorious for giving adverse reactions”.

Exact figures are difficult to nail down.

ZIn a 2022 study at a KwaZulu-Natal hospital, nearly half of all snakebite patients who received the SAIMR polyvalent antivenom went into anaphylactic shock. In a second research paper at the same hospital, this only happened to 23% of patients. These studies rely on small samples, which might explain the different results – but it’s clear that side-effects are very common.

Additionally, the SAVP products are expensive. A study conducted in Kenya found that the price of the SAIMR polyvalent treatment and the Boomslang drug far exceeded that of other antivenom products which were available in the country. In fact, the SAVP antivenoms were nearly triple the price of the next most expensive product (see part 1 of this series for a list of current prices).

A third issue relates to the lengthy production timelines.

Antivenom is made by administering small amounts of snake venom into a horse. Over time, the animal becomes “hyperimmunised”, meaning its immune system produces lots of antibodies that combat the venom. The horse’s blood is then collected, and the liquid part of the blood, called plasma, which contains the antibodies, is filtered and stored in ampoules. The result is antivenom.

But this takes a long time, and the SAVP is South Africa’s only manufacturer. This means that any slip-up can leave the country vulnerable to shortages of the kind that occurred last year.

Johan Marais, the head of the African Snakebite Institute explains: “It takes nine months to hyperimmunise a horse – if you make any mistakes [during that process] it’s going to take another nine months to get the horse hyperimmunised”.

Even once that’s done, “you can only bleed nine litres every two months,” he says, “so any minor flaw in the system has major ramifications in the foreseeable future”. This is particularly concerning because the SAVP has been facing production challenges in recent years, according to Marais.

In response to questions about how the SAVP is planning on avoiding more shortages, Gcukumana told Spotlight that “infrastructural challenges that had a negative impact on antivenom production have been addressed over recent months”.

In particular, he stated that the SAVP has “procured additional generators and uninterruptible power supply systems that have assisted [it] in meeting the energy demands of the manufacturing process even during power outages.”

Clearly, the SAVP-made antivenoms are a life saver for many patients, but the side-effects, the high price tag and the long production timeline, which leaves the country vulnerable to shortages, means that the product isn’t ideal. Fortunately, scientists are working on solutions.

'NEXT-GENERATION ANTIVENOMS'

Dr Constantinos Kurt Wibmer is a South African scientist at the Wits Health Consortium who is attempting to develop a new monoclonal antivenom. Wibmer explains that current antivenom products are polyclonal, meaning they’re composed of lots of different kinds of antibodies, each of which targets different toxins within snake venom. Additionally, these antibodies will attach to different binding sites on each toxin.

This has an upside, says Wibmer: “Venom has 50 or so toxins… so that’s why a polyclonal product has historically been the thing to go for, because you have 50 or 100 different antibodies hitting all those different toxins.”

However, this “shotgun approach”, as Ainsworth calls it, also comes with problems. One is that not all of these antibodies are actually specific to the snake toxins. Indeed, according to Wibmer, 80 to 90 percent of the antibodies in traditional polyclonal products are ordinary horse proteins that don’t play any role in neutralising snake venom.

The result? When antivenom is injected into a person, their body is flooded with various animal proteins which the immune system recognises as foreign. This can elicit a severe immune response, which can cause a person to go into anaphylactic shock.

The new monoclonal antivenom which Wibmer is trying to develop is quite different. He explains that rather than making antivenom by collecting horse plasma that contains many different antibodies, he starts by finding the cells that actually make those antibodies. Essentially, his team takes hyperimmunised horses – the exact same ones used by the SAVP – and then isolates the antibody-producing cells from their blood.

The cells they look for make particular kinds of antibodies that target “certain pockets” that are found on the surface of multiple toxins present in different snake venoms. And while these antibodies still come from horse cells, Wibmer and his team can alter the cell DNA so that the antibodies that they make are more humanised. They thus look less foreign to a person’s immune system.

Consequently, if Wibmer’s monoclonal antivenom was successfully developed, snakebite patients would no longer need to inject an array of foreign horse antibodies that trigger a massive immune response. Instead, they would receive a small number of humanised antibodies that were all highly specific to venom. Consequently, patients wouldn’t get the same nasty side-effects that currently comes with the treatments.

Additionally, since it’s made in the lab, the quality and safety of each batch would be consistent – unlike current antivenoms which can vary from vial to vial.

According to Wibmer, we’re still years away from monoclonal antivenoms. But if successfully developed, such products could cut down on the time it takes to make antivenom, helping South Africa avoid more shortages of the drug in the long run. According to Wibmer instead of having to wait nine months to immunise a horse “we [could] walk into the lab, start a batch, and scale up production over days or weeks as needed”.

This would be “much, much quicker,” says Wibmer “and it is always consistent.”

This is part 2 of a Spotlight special series on snake antivenom in South Africa. You can read part 1 here.

This article first appeared on Spotlight. Read the original article here.