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Making sense of the complex world of vaccine development for Covid-19

Making sense of the complex world of vaccine development for Covid-19
A a medical worker holds a sample in preparation for the country's first human clinical trial for a potential vaccine against Covid-19 at the Baragwanath Hospital on 28 June in Soweto.(Photo: Gallo Images / Beeld / Felix Dlangamandla)

Once a successful vaccine is identified, global supply chains will need to get into high gear to produce the billions of doses that may be needed. But practically, it is hard for countries and international organisations to know which kinds of production facilities to ramp up without knowing which types of vaccine will emerge victorious.

When the US-based pharmaceutical company Moderna announced in May that its “mRNA-127” coronavirus vaccine showed promising results in early clinical trials, its stock price soared. This chimera of a reprieve from global anxiety about the pandemic, and the tempting prospect of a new-new normal sent a shock wave through the stock market because countless survivors of months of lockdown around the world rejoiced that finally there may be an exit strategy. But (sorry), not so fast.

We are — inescapably — still in for a long haul to a Covid-19-free existence. The science community’s response to Moderna’s announcement based on tenuous early results was less euphoric than the stock market’s (the broader scientific community is sceptical and the scientists from the US National Institute of Allergies and Infectious Diseases (NIAID) behind Moderna’s vaccine uttered not a word) confirming — as many experts have said and as we are tired of hearing — that it’s probably a 12- to 18-month wait for a viable vaccine. Why, given the rapid advances of Moderna and several other vaccines that are by now in final-phase clinical trials?

In their rush to grab our anxious attention, dumbed-down broadcast news programmes and catchy headlines give us the short answer, short-circuiting two basic truths: first, a vaccine is not necessarily a silver bullet, and may only reduce the chance of infection or serious illness, rather than eliminate that likelihood; second, vaccine development is a long, complex process that involves performing progressive phases of clinical trials whose “slowness” is because of the need to ensure long-term safety in patients. “Do no harm” must prevail over speed.

But it is worth understanding the long answer, to temper unrealistic expectations, and to drive home the necessity of being steadfast in our prevention measures while holding on to hope and optimism.

For any vaccine to get to market, what needs to happen is:

  1. Find a vaccine that works (this is not obvious — historically, 90% of potential vaccines fail in trials);
  2. Conduct clinical trials in three standardised, progressive phases to test that it is safe and that it works (more on this below);
  3. Manufacture enough of the vaccine to distribute globally, that is, billions of doses;
  4. Support poorer countries’ purchase and distribution of the vaccine; and
  5. Ensure that all people who need it can afford it and can access it (perhaps the trickiest step of all).

Clinical trials

The clinical trials for any new medicine or vaccine go through at least four stages: pre-clinical, Phase I, Phase II and Phase III (and sometimes a Phase IV). Each stage has a different purpose and the vaccine candidate only continues on its path if it is successful at each stage.

Pre-clinical trials, usually done only in animals, establish safety and “efficacy” — that is, does it work? Phase I tests — in humans — safety, dosage, and for evidence of some immune response. These tests are small-scale, usually 20 to 100 people. Phase II is the “real” efficacy stage, where the optimal dose is tried on a larger group (a few hundred volunteers, and the nature of the immune response and side-effects are further examined. This is the stage that filters out the “really promising” from the “initially promising”.

Phase III is the real proving ground for a vaccine, during which it is tested on hundreds or thousands of people, often in several different locations, to evaluate whether it works under “natural” disease conditions, over a longer period of time than those allotted to Phases I and II (usually several months or years). Phase III also has a “control” (placebo) arm so that the vaccine’s results can be assessed relative to “normal” rates of infection. If the vaccine proves still to be safe and to work over a longer duration, the manufacturers can apply to their country’s regulatory authorities for a licence to produce and market it.

The leaders of the pack

A dizzying array of vaccines for Covid-19 are in development, “genetic” (DNA- or RNA-based), viral vector (a virus as delivery mechanism), and protein-based, among others. Overall, there are at least 160 “candidate” vaccines, with 22 already in human trials. The different approaches may appear confusing, but basically all vaccines work by provoking an immune response.

The frontrunners at the moment include NIAID/Moderna, BioNTech/Pfizer, and the University of Oxford/AstraZeneca (usually a pharmaceutical company partners with the researchers to manufacture if and when the vaccine proves successful).

The Oxford/AstraZeneca vaccine — for which South Africa is one of the Phase III test sites, along with Brazil — is a “non-replicating viral vector” vaccine, which uses a harmless “host” virus to deliver the genetic sequence of a protein on the surface of SARS-COV-2 (the virus that causes Covid-19). This vaccine’s relative speed is due to development that happened years ago for previous coronavirus outbreaks (SARS in 2002-2004, Mers in 2012). When those outbreaks were contained, the coronavirus vaccine development was halted — but the vaccine had already passed human safety trials. The leaders of this effort have said they could potentially deliver “emergency” doses by October (if Phase III goes well).

The Moderna/NIAID candidate is a “genetic” vaccine, specifically a “messenger RNA” (mRNA) type. But there has never yet been a DNA or RNA vaccine candidate approved for human use, anywhere — and one implication of this is that even more lengthy and stringent monitoring of the medium- and long-term effects of this vaccine on trial populations may be necessary. (This is often what happens in Phase IV, which would be circumvented if a vaccine for Covid-19 were licensed for “emergency use”, as Moderna’s or Oxford’s might be.)

Germany’s BioNTech/Pfizer vaccine, whose Phase I/II trial showed an increase in volunteers of coronavirus antibodies with three doses, is another mRNA vaccine. Pfizer’s CEO has suggested that they could start to deliver the vaccine in October, with hundreds of millions of doses by the end of 2020, and up to a billion by the end of 2021.

Which brings us to the question: who gets those first early, limited doses?

Equitable access?

Obviously finding a vaccine that works is important — but equally important is ensuring that everyone who needs it can access it. The human-rights principle at the heart of this idea seems obvious now — but in the 1990s, when HIV began cutting a swathe through the developing world, especially Africa, the fact that antiretrovirals to treat it were only affordable for the wealthy “north” remained somehow politically acceptable for about a decade. “Treatment for the north” and “prevention for the south” was the status quo. (A global groundswell of outrage, in full flood at the Durban 2000 AIDS conference, led to a seismic shift in the world’s view of equitable access to healthcare.)

Once a successful vaccine is identified, global supply chains will need to get into high gear to produce the billions of doses that may be needed. But practically, it is hard for countries and international organisations to know which kinds of production facilities to ramp up without knowing which types of vaccine will emerge victorious — manufacturing an RNA vaccine instead of a non-replicating viral vector, say, is not analogous to simply changing the mould in a biscuit factory. This means there will, at least initially, be a production bottleneck, until the specific vaccine is identified. This also means that politics (or diplomacy) rather than pure “need’ will determine who gets first dibs.

On top of that, global vaccine production has “no excess capacity,” says Paul Stoffels, the head of Johnson & Johnson (which along with GSK, Pfizer and Sanofi is one of the biggest commercial vaccine manufacturers globally.) This also means that new production facilities will need to be built to safeguard the production of the vaccines the world continues to need and which are already reported to be under threat, with many routine immunisation programs halted in some countries because of Covid-19.

There is a global collaboration attempting to pre-empt these kinds of problems, in the form of the WHO-convened Access to Covid-19 Tools Accelerator (ACT-A). In May, most of the world’s major political powers and health organisations agreed to collaborate on the development, production, and equitable access to everything that is needed to prevent, detect, and treat Covid-19.

The Oslo-based Coalition for Epidemic Preparedness (CEPI), which was created to accelerate the development of vaccines for all infectious diseases, is a partner in ACT-A and is supporting several different Covid-19 vaccine efforts, including Oxford’s, whose manufacturing partner AstraZeneca has said that the vaccine will be made available at cost during the pandemic. Gavi, a global vaccine alliance that finances vaccines for 70+ of the world’s poorest countries, will have a leading role in the global distribution of a Covid-19 vaccine.

Globalisation has been good for this virus (from the virus’s point of view), but it has also been good for global solidarity in efforts to fight it. The nature and extent of international collaboration (with the notable exception of the increasingly petulant US president’s refusal to share) has heralded a step change in a collaborative approach to global health as a public good. In principle, at least.

It may be that Moderna or Oxford’s vaccines will beat all records and get to market at scale later this year — but as World Health Organisation Director-General Tedros Adhanom Ghebreyesus has said, the ultimate measure of success will be not how fast we can develop tools to fight Covid-19, but how equally we can distribute them. DM/MC

Adèle Sulcas writes about global health, food systems, and the wine industry. She has worked at the Global Fund to Fight AIDS, TB and Malaria and the World Health Organisation, and is an adviser to Internews’ Pandemic Media Mentors.

Gallery

"Information pertaining to Covid-19, vaccines, how to control the spread of the virus and potential treatments is ever-changing. Under the South African Disaster Management Act Regulation 11(5)(c) it is prohibited to publish information through any medium with the intention to deceive people on government measures to address COVID-19. We are therefore disabling the comment section on this article in order to protect both the commenting member and ourselves from potential liability. Should you have additional information that you think we should know, please email [email protected]"

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