Science Talk

Fast and Furious. Can we trust the speedy development of Covid-19 vaccines?

One major issue that has been raised is whether vaccines developed in record time can be safe. PHOTO: AFP

SINGAPORE - Singapore moves into phase three of reopening its economy on Monday (Dec 28).

For life to become more normal, and for businesses to get back on their feet, more people need to become immune to the virus.

This can happen only through mass vaccination.

As Covid-19 vaccines become progressively available, the Ministry of Health has urged eligible residents to be vaccinated, but this is voluntary.

The success of the vaccination programme depends on who is willing to get the shot.

Worries about safety and efficacy will undermine the strategy, and one major issue that has been raised is whether vaccines developed in record time can be safe.

Speed and safety

There are several reasons why the current slate of Covid-19 vaccines could be developed at breakneck speed while meeting the scientific and regulatory rigour necessary for use on the population.

First, the coronavirus is a well-known pathogen to those in the infectious disease community.

Those who remember the severe acute respiratory syndrome outbreak in 2003 may know that that particular virus is a close cousin of the present Sars-CoV-2 virus, with a high degree of genetic similarity, and sharing many features and proteins.

Armed with this knowledge, researchers were able to rapidly develop diagnostics and make early attempts at antivirals to combat this current disease.

Likewise, for vaccines, researchers were very quickly able to target proteins of interest, with a reasonable amount of assurance that they were relevant.

For example, the coronavirus uses its unique, crown-shaped spike protein to infiltrate a cell and replicate. Thus, the spike protein is the focus of most Covid-19 vaccines as it is the part of the virus that enables it to enter our cells.

By February, the vaccine effort was already in full swing right across the globe.

Second, the scale of partnership and collaboration across all the different players was at an unprecedented level. Collaborations that would normally take months or even years to forge were inked in days and weeks.

A high-profile success story is the partnership between Pfizer, a large United States-based pharmaceutical company, and BioNTech, a small German biotechnology firm.

This combined the clinical development and manufacturing might of a big pharma powerhouse with the novel mRNA vaccine discovery platform of a small and nimble biotech.

Another example is the collaboration between Sanofi Pasteur and GlaxoSmithKline, normally rivals in the field of vaccines, combining a protein sub-unit vaccine from the former with a pandemic vaccine adjuvant of the latter. (An adjuvant is an ingredient used to create a stronger immune response.)

The breathtaking openness and willingness of companies to bring together ready-made know-how and technologies have significantly accelerated the pace of development.

Third, drug and vaccine development comprises several key steps, which are usually performed sequentially. It starts with building an understanding of the pathogen and its biology, then the discovery of likely drug or vaccine candidates, the setting up of animal models, early drug material production, toxicity studies, clinical Phases 1, 2 and 3 (where the drug's or vaccine's safety and efficacy are tested on people) then commercial-scale manufacturing and distribution.

Progressing from each of these steps to the next requires significant and ever-increasing investments, with the knowledge that failure lurks around the corner.

Under normal circumstances, companies are quite leery of moving forward until a proper study and analysis of data from the prior steps are completed. Months can pass between the conclusion of one phase to the start of the next, as future investments depend on the success of each stage.

Given the usual high rate of attrition and failure of drug and vaccine development, and absent a pressing societal imperative, this prudence is usually warranted.

However, given the urgent need to end the pandemic, much of the work done on the leading vaccine candidates has been executed in an overlapping fashion, or in parallel.

Pfizer-BioNTech progressed multiple candidates to early lab testing to narrow down those that elicited the best immune response; clinical studies were planned and sites booked well ahead of the completion of animal toxicity studies that facilitated human dosing; clinical Phase 1, 2 and 3 studies were overlapped to provide seamless transitions from exploratory to confirmatory trials; and large commercial-scale manufacturing capacities were set up ahead of time in anticipation of successful trial outcomes.

The Pfizer headquarters in New York. A high-profile success story about the Covid-19 vaccine effort is the partnership between Pfizer and BioNTech. PHOTO: AFP/GETTY IMAGES

All this work performed "at risk" has enabled the completion of a vaccine programme from concept in early February to delivery to patients this month.

Breakneck speed indeed, but replete with all the scientific, medical and manufacturing rigour demanded of such products.

Fourth, to drive the speed of the development effort, generous funding, or assurance of it, had to be forthcoming.

It should be noted that while a fair amount of discovery work can occur in academic as well as company labs, when it comes to conducting large multinational clinical trials, and massive-scale manufacturing and distribution to the tune of hundreds of millions of doses, it is clearly the province of private enterprise.

To encourage companies to move with speed into expensive late-stage development and manufacturing, some assurance of cost recovery is necessary.

To the credit of many public agencies worldwide, this was recognised early, and unprecedented amounts of public funding were committed to supporting the development and manufacturing of vaccines by selected companies.

For instance, Operation Warp Speed, a private-public partnership initiated by the US government, has committed in excess of US$7 billion (S$9.3 billion), distributed among the likes of Johnson & Johnson, Moderna, Novavax and AstraZeneca/Oxford University.

This funding has supported late-stage development and large-scale manufacturing while assuring early access to vaccines upon approval.

Other governments have pursued bilateral advance purchase agreements with individual companies, guaranteeing supply of some volumes of vaccine for the countries in the case of successful development, in exchange for some financial mitigation for the company in the event of failure.

In addition, non-profit organisations such as the World Health Organisation, Coalition for Epidemic Preparedness Innovations and vaccine alliance Gavi, through the Covax facility meant to ensure equitable vaccine access worldwide, provide funding to companies to mitigate risk for development and assure equitable supply to both low- and high-income countries.

The role of regulators

Fifth, the role of regulators as facilitators for rapid guidance and review is critical.

Under normal drug and vaccine development paradigms, major regulatory agencies tend to have set points of interaction with companies to provide guidance on development plans, and will receive full dossiers at the end of development programmes, to be examined in their entirety.

Agencies like the US Food and Drug Administration (FDA) and European Medicines Agency may then also conduct audits at clinical study sites and manufacturing plants prior to issuing licensing and marketing approvals.

Agencies may receive dozens to hundreds of new drug applications each year, and such processes, though not the speediest, allow for a predictable cadence of work and manageable throughput for any given number of staff.

With Covid-19, major regulatory agencies around the world, including Singapore's Health Sciences Authority (HSA), have activated accelerated pathways to speedily review and approve novel vaccines.

The FDA has an emergency use authorisation pathway, and the HSA recently introduced the Pandemic Special Access Route (PSAR) for the interim authorisation of critical novel vaccines.

These allow companies with robust Phase 3 data to apply for emergency use of their products.

To further expedite reviews, regulators have also been accepting data on a rolling basis, so that as the final trials come to a conclusion, the review of prior information may already have been completed.

Both Pfizer-BioNtech and Moderna have been granted emergency use authorisation by the FDA for their Covid-19 vaccines, the FDA having held the two advisory committee meetings a week apart, on open televised platforms.

The HSA has granted interim authorisation to the Pfizer-BioNtech vaccine via the PSAR pathway.

Both Pfizer-BioNTech and Moderna have provided robust dossiers with data describing excellent efficacy and safety, for up to about two months of observation from the last dose.

The vaccines' efficacy of protection from Sars CoV-2 symptomatic infection of over 94 per cent, across a wide range of ages, including the elderly, has exceeded even optimistic expectations.

These studies were enormous, enrolling in excess of 30,000 patients each, and dosing half of those test subjects with active vaccines.

A fair proportion of participants receiving the vaccines experienced what we could call symptoms of "reactogenicity". These include fever, muscle aches and fatigue, and arise from an immune response to the vaccination, lasting a few days.

There were scattered reports of Bell's palsy in the trials, and there have been reports of severe allergic reactions in a small number of the vaccinated.

Data on these infrequent events is evolving and vaccination guidelines will require, for now, close observation of vaccine recipients in the immediate period after receiving the dose.

Although it was not presented in any detail at the advisory committee meetings, the two companies also provided pre-clinical and manufacturing-quality data to the regulators.

What is missing

The long-term effectiveness and safety of these vaccines are yet to be fully investigated.

Clearly, one-year safety data in the human setting can come only a year after the last dose; there is just no way to accelerate that process. However, this is not to say that certain inferences cannot be made about potential long-term effects.

The mechanism of the vaccine action, biology of the disease and supporting animal data can all provide clues and anchors for scientists to make useful projections about potential long-term side effects.

Long-term efficacy data will become fuller with the passage of time, but initial indications are that the vaccines are likely to be protective for a good duration.

Another drawback of accelerated development is that full stability information about a vaccine formulation may not be completely mapped out, or the formulation itself may not be fully optimised.

We hear about the exacting cold chain requirements for the Pfizer-BioNTech vaccine, which demands minus 70 deg C storage. This is possibly because the stability of the molecule at higher temperatures has yet to be fully characterised, and it has been reported that Pfizer is looking to develop a powder form of the vaccine, which will most likely be stable at higher temperatures.

The pandemic has wrought a devastating toll on society, both on those affected directly by infections and indirectly through economic shutdowns. Vaccines offer a safe way to protect the uninfected and also provide a path to recovery for many sectors of the economy.

The unprecedented speed of Covid-19 vaccine development is in no way due to any short cuts taken by the researchers, companies or regulators. The scientific methods have been sound, pivotal clinical trials have been large and well-conducted, and data provided to date has been full and rigorous.

With some caveats around the lack of long-term data, the findings of the first two vaccines approved by the FDA indicate highly effective shots with good safety profiles.

Enough to provide a glimpse of light at the end of the tunnel, and for us to roll up our sleeves and take our first steps towards it.

About the writer

Dr Danny Soon is Chief Executive Officer at the Consortium for Clinical Research and Innovation, Singapore (Cris) and concurrent Executive Director at the Singapore Clinical Research Institute (SCRI). A veteran of the pharmaceutical sector, he is a member of the Ministry of Health Expert Committee on Covid-19 Vaccination.

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