How and why pharmaceutical companies have not caught up with the Ebola outbreak in Uganda

(ORDO NEWS) — This fall, Uganda was hit by a new wave of Ebola. The strategy is the same every time: isolate all those identified, treat symptomatic ones, vaccinate all contact ones.

Only this time another type of ebolavirus has come – there is neither a proven vaccine nor a proven cure for it. And, it seems, until they appear.

Ebola is an infection that has long been known and well studied, unlike covid. A census of its outbreaks has been conducted since 1976, and there are already several dozen lines in this list.

In addition, almost every year, a new case of infection, a laboratory incident involving ebolavirus, or just a suspicious patient is reported from some country in the world.

And yet, when, at the end of 2013, two-year-old Emil from the Guinean village of Meliandu (we talked about him in the text “Gifts of Love”) triggered a new outbreak of Ebola, having become infected in the hollow of a tree, it turned out that the doctors had nothing to offer him or his family.

As it was

A group of scientists in Winnipeg, Canada began developing a vaccine for ebolavirus back in the 2000s. They chose a vector platform: they took the vesicular stomatitis virus, dressed it in proteins from the shell of the ebolavirus, and conducted preclinical tests on cynomolgus monkeys.

After vaccination, experimental macaques were already infected with a real pathogen, and with a lethal dose. But no one died from it – in the vaccinated animals, even the temperature did not rise.

Further, according to all the laws of clinical trials, this prototype had to be tested on humans. But there were no people willing to organize such tests. Developing and testing vaccines is expensive.

And all known outbreaks of fever did not go beyond the African continent, and the number of deaths from it did not exceed several hundred. Therefore, the fight against it did not look profitable.

The situation has not changed in the spring of 2014. When there were already under a hundred cases in Guinea, and the epidemic spread to the neighboring countries of West Africa, the vaccine developers turned to the WHO – but they were told that everything was not so bad, it was too early to talk about vaccine trials, and, moreover, in Guinea there is no necessary infrastructure to properly organize them.

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This is how Ebola spread around the world during the mid-2010s outbreak
How and why pharmaceutical companies have not caught up with the Ebola outbreak in Uganda 3
Map of the spread of the Ebola epidemic in West Africa by November 30, 2014

Six months later, about two thousand people had already died from the fever, and the WHO changed its mind. On August 8, she declared the outbreak an emergency of international concern, and a couple of days later, the Canadian government promised to donate the Winnipeg vaccine to the organization.

But it’s just that there were no people who wanted to test it, and it didn’t appear. WHO had to knock on the doors of all the major pharmaceutical companies in turn. In October, she reached out to Merck & Co, at the end of November the company bought the license for the vaccine and began preparations for testing.

A lot of testing was needed, since no one had previously tested the prototype vaccine on humans (except for one employee of a German laboratory who pricked herself with a needle infected with ebolavirus). It was necessary to carry out all three phases: safety, immunogenicity, efficacy.

To shorten the time, the first phase was started in several African countries, Europe and the USA at once. While this data was being processed, Merck & Co employees were already planning the second phase, combined with the third.

It started in April 2015. And it looked pretty unusual, at least compared to current coronavirus research. Participants were vaccinated according to the principle of the ring: that is, those who were in contact with the sick people received the vaccine, and then the contacts of the contacts.

At the same time, half were vaccinated immediately, and the other half after three weeks (the standard incubation period for ebolavirus; if infection occurred immediately, then symptoms should appear by this time). The second group of participants was used as a control.

By July, it was clear that the vaccine was working. It took a little less than a year to finally get the drug off the shelf, refine it, manufacture it, and test it.

Today, no one is surprised at such a speed – the developers of the first coronavirus vaccines have kept within nine months, and they started almost from scratch, with a completely unfamiliar virus. But seven years ago, this “sprint” became the fastest in the history of pharmacology.

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Incidence graph at the epicenter of the 2014-2016 Ebola epidemic

True, by the time it became clear that the vaccine was working, there was practically no one to vaccinate her. The incidence crossed the peak in the fall of 2014 – at that moment WHO was only looking for a manufacturer for a vaccine – and by the spring of 2015 it had fallen several times.

Thousands of people have died, tens of thousands have recovered. The testers have already worked with the last hundreds of carriers of the virus and their close contacts.

Therefore, it was possible to complete the trial of the drug only in Guinea. In neighboring Liberia and Sierra Leone, there were simply not enough patients for a full-fledged study. And other companies – which also took part in this vaccine race – did not get anyone at all.

Only Johnson & Johnson managed to slip through the closing doors: she began to recruit volunteers in the fall of 2015. Even then it was clear that the effectiveness of the drug could not be reliably assessed, but the pharmaceutical company nevertheless conducted the first and second phases of the trials, having received data on safety and immunogenicity.

As a result, more than ten thousand people died from hemorrhagic fever in West Africa in more than two years, and the pharmaceutical industry purchased one and a half vaccines.

In the following years, in smaller outbreaks, the drug from Merck & Co was already used routinely, and in 2019 it received official approval from regulators – first in Europe, then in the USA. Johnson & Johnson had to take a little longer and get themselves additional tests during the outbreak in the Democratic Republic of the Congo. But in 2020, her drug was approved.

Now, it would seem, with the next outbreaks it should have gone easier.

As it is

On September 20, 2022, Ugandan authorities reported a new outbreak of fever in Mubende district – as soon as they received a positive test from the first patient.

But it is possible that the outbreak began even earlier – it just takes time for doctors to make sure that we are talking about Ebola (excluding malaria in the first place, and then other fevers), and the Ministry of Health decided to sound the alarm.

In two weeks, Ebola spread to another four neighboring districts, and the number of patients has already gone to dozens.

It would be possible to immediately uncover two ready-made vaccines, and at the same time a medicine – a cocktail of antibodies, which also managed to be approved since the last time. But another type of ebolavirus came to Uganda: not Zairian, as during the epidemic of 2013-2016, but Sudanese.

It causes the same disease – but quite different from its relative at the genome level. So much so that the vaccine (as well as the cure) for the Zairian ebolavirus against the Sudanese species does not work.

And now the story repeats itself from the beginning: since the Sudanese ebolavirus was much less common for epidemiologists and did not cause such large outbreaks before, it was not of interest to pharmaceutical companies. This means that no vaccine or cure has been prepared for him.

This time, the WHO reacted faster. Within a week of the Ugandan alarm, the organization announced that it was planning to conduct clinical trials of new vaccines. The organization promised that they would begin in a couple of weeks – at the very least, in a month.

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Ebola spread in Uganda by 7 November 2022
WHO

There were two applicants at once: the American Sabin Institute (it inherited the developments of the GalaxoSmithKline company, which they did not have time to check in 2015) and the British Oxford. The third could be Johnson & Johnson. All of them, like last time, had draft vaccines on their shelves – now from the Sudanese ebolavirus.

But none of the blanks turned out to be really finished. At the Sabin Institute, the vaccine was in the form of a “semi-finished product” – that is, it still had to be diluted, packaged and packaged.

The Oxford Institute simply did not have enough doses – and they had to urgently establish production. J&J had a supply on hand – but she still didn’t decide if she was interested in getting involved in this race.

A month passed, the tests promised by the WHO did not begin, and Merck & Co suddenly remembered that she, too, had some developments lying around on the shelves. Journalists still have not been able to find out why the company representatives were silent about this earlier.

They only told Science magazine that they had accidentally kept the drug from 2016. Technically, it had already passed its expiration date, and it should have been disposed of – but for some reason this did not happen.

Merck&Co promised to check the quality of expired doses and send them to Uganda as well. True, this vaccine has never been inside a living person, which means that tests for it will have to start from scratch.

While WHO, Ugandan authorities and pharmaceutical companies were negotiating, calculating doses, setting up production and agreeing on test protocols, a lot of time passed. And the organizers of the trials were afraid that they might not be in time again, because the patients are gradually running out.

How will it be next

The developers of coronavirus vaccines were also afraid of the same thing – already in the second year of the pandemic, they complained that the population of unill and unvaccinated people they needed was rapidly declining.

Then some manufacturers even abandoned the control group in their trials (we wrote about this in the text “It will be worse”). But the covid pandemic dragged on: new options appeared, immunity from old vaccinations gradually wore off.

And now new manufacturers may turn out to be successful if they rush in and come up with a more effective way to protect people from omicron, or even from several variants of the coronavirus at once.

With Ebola, the situation is much more complicated: it flares up quickly, but it also burns out just as quickly. And you need to act very cleverly to grab her by the tail.

Part of the reason is that ebolavirus is not as contagious as respiratory infections. Part of it is that it’s more deadly, and the symptoms of a fever are much harder to miss or mistake for a mild ailment. In part, this is because local authorities, trained in previous outbreaks, have learned quite well how to take effective epidemiological measures.

They already know in which situations Ebola spreads especially well – for example, during farewell rituals, for which relatives exhume the bodies of those who died from a fever, and also in private clinics, where patients go first thing, not trusting public hospitals.

And they easily decide on lockdowns: this time, for example, the two most “hottest” regions were closed for entry and exit, public transport was canceled and a curfew was introduced. And they are not too lazy to look for those

So there are fewer and fewer free-roaming carriers of the virus. This time, in addition, WHO changed the test protocol. Its experts reported that, according to their data, it is close contacts of sick people that are most often infected, and the turn rarely comes to second-order contacts.

Therefore, only first-level contacts are planning to vaccinate. And this means that there are even fewer people suitable as test participants.

On December 2, the Ugandan Ministry of Health approved trials of three vaccines. And on the same day he announced that the last patient with Ebola had been discharged from the hospital. This means that the testers have very little time left.

The incubation period for fever is approximately 21 days. The last confirmed case was recorded on November 13. And if new patients do not appear before December 25, the Ministry of Health will be able to announce that the outbreak is over.

And to sum up (at least this is how it looks today): 164 cases, 87 survivors (or 142 and 86, respectively).

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Some experts consider the numbers given in the poster to be underestimated because they do not include unconfirmed infections and deaths

There are literally a few hundred contacts of the first level in the country. It is not clear how three vaccine manufacturers will be able to grab onto this tail at once.

Perhaps lucky, like last time, the fastest. And this seems to be the Sabin Institute – on December 8, the first batch of his drug arrived in Uganda. Vaccines from Oxford and Merck&Co are still on the way.

So far, the test organizers are in no hurry to freeze projects and make forecasts. The Ministry of Health of Uganda is also not rushing things – after all, they have already attracted several million dollars for these studies.

In extreme cases, it will be possible to collect at least some data – and they definitely will not be superfluous.

For example, you can test whether Merck&Co’s Sudanese ebolavirus vaccine is just as safe and immunogenic as the Zairian one. And if so, then this argument can be used later to convince regulators to approve it as soon as possible.

From the start of the outbreak to the arrival of the doses, only two and a half months passed, but this is too long. So the next time you have to act even faster. Therefore, even if the tests do not take place, the organizers will have something to do in anticipation of the next outbreak.

Attract new investments, maintain production, debug the system for storing vaccines, check their quality from time to time and throw out the unusable ones. Draw up test reports and certify them with the local regulator.

But all these costs must one day be justified – judging by everything we know about Ebola, the next outbreak is bound to happen.

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