The modern space race: Vaccine rollout and the regulatory regime

We might say that the last few months of 2020 bore witness to the 21st century equivalent of the space race. Across the world, biopharmaceutical companies have been racing to safely launch a COVID-19 vaccine, with the eyes of the media carefully following every twist and turn.


First published in our Biotech Review of the year – issue 8.

Humanity has not been slow to embrace the vaccine story: millions of pounds have been invested; millions of hours of research have been conducted; millions of words written; and millions around the world have eagerly awaited a successful outcome. Where, 12 months ago, vaccine technology would seldom prick the public consciousness, it has now become front page news. And whilst mRNA might not be as easy as 123, it has overtaken ABC and others to become one of the acronyms of the year, whilst interest in the vaccine approval process has never been greater.

Crucially, though, the rollout of the COVID-19 vaccine could provide a useful precedent for how future vaccines, not least novel nucleic or viral vector varieties, can be swiftly brought to market at a time of acute public need.

From Jenner to Pfizer: what is a vaccine?

Vaccines work by taking advantage of the body’s immune system, and its exquisite ability (when working properly) to distinguish between friend and foe, and remember those foes it has previously seen. Vaccines expose the body to the invading pathogen so that the body then produces antibodies to the foreign material in a ‘safe’ environment, in the sense that the pathogen is presented in such a way that it is unable to infect the individual.

After inoculation with a vaccine, the development of antibodies primes the body so that when it is exposed subsequently to the invading pathogen, the immune response is significantly amplified, allowing the body to fight off the pathogen without deleterious consequences.

Further, mass vaccination protects populations as a whole, as it reduces the pool of susceptible individuals who are then able to re-transmit the infecting agent. In the most successful cases, vaccination can lead to complete eradication of the disease, as has heroically been achieved with smallpox.

Coronavirus disease 2019 (COVID-19) is, as its name suggests, caused by a virus, namely SARS-CoV-2. Vaccines against a virus have typically involved presenting to the body either the whole virus or subunit pieces of the virus (often fragments of protein), to trigger an immune response. There are four different routes for presenting the foreign viral material to the immune system that are generally used and have been investigated with COVID-19.

Where the whole virus is issued, steps are taken to prevent the virus infecting the host. This involves either a live attenuated form, using a weakened form of the virus, or an inactivated virus, wherein genetic material of the virus has been removed/destroyed so as to prevent it from replicating in the body. In both cases, large amounts of virus are produced in the lab (which can be a disadvantage of this route given the risk of an unintended escape), which is then modified by attenuation or inactivation. These two types of whole virus vaccines are well-established in terms of technology and pathways to regulatory approval, and are generally relatively easy to manufacture. The Sinovac and Sinopharm vaccines are examples of an inactivated whole virus vaccine developed for COVID-19.

The subunit vaccine uses a different method of introducing viral material into the body. Purified pieces of viral material selected for their ability to elicit a strong immune response are used. The subunit can be part of a protein, a polysaccharide, or a conjugate between a protein and polysaccharide. In the case of COVID-19 vaccines, the ‘spike’ protein of the virus has generally been chosen to develop a protein fragment. As these fragments cannot cause disease, the risk of side effects is minimised. These types of vaccines are cheap and relatively easy to produce, and again have a well-established route to regulatory approval. The viral material is grown in living organisms, by genetically engineering bacteria or yeast (not the virus) to produce quantities of the fragment in question. The fragments are purified, and often need to be complemented by an adjuvant to boost the level of immune response. The Novavax COVID-19 vaccine is an example of a protein subunit vaccine.

Nucleic acid vaccines are a relatively new technology, and involve using DNA or RNA encoding of the antigen of interest. Prior to COVID-19 no nucleic acid vaccines had been approved for human use, although several DNA vaccines had been approved for animal use. Both types involve introducing genetic material into the host body’s cells, so that those cells transcribe and/or translate the genetic material into protein, which is then presented on the host cells to stimulate the immune response.

With DNA vaccines, a piece of DNA is inserted into a bacterial plasmid, which is then injected into the individual, along with one of a number of technologies to assist the plasmid to penetrate into the host’s cells.

RNA vaccines encode the protein of interest in messenger (mRNA) or self-amplifying RNA (saRNA). Unlike bacterial plasmids containing foreign DNA, the RNA in RNA vaccines is transitory as the RNA cannot replicate or integrate into host genetic material, and is therefore seen as safer than DNA vaccines. The RNA encoding the viral protein is injected alone, encapsulated with nanoparticles or driven into cells using similar techniques as for DNA vaccines. Due to the nature of DNA and RNA vaccines, it can be very quick to develop these once the viral DNA or RNA is known. In the case of COVID-19, its RNA was sequenced at a very early stage, allowing rapid development of mRNA vaccines.

Both types are relatively easy to manufacture, although as most readers will be aware, extreme (i.e. ultra-cold) storage conditions for nucleic acid vaccines are often needed to protect the genetic material to be injected. Examples of mRNA vaccines developed for COVID-19 are the Pfizer-BioNTech and Moderna vaccines that have received significant recent press coverage.

A final class of vaccine being developed for COVID-19 are the viral vector vaccines. These are similar to nucleic acid vaccines in that they do not directly introduce the whole or parts of the virus in question to stimulate an immune response, but instead use the body’s own cells to manufacture the protein in question. In this case, genetic material encoding the protein in question is inserted into a different, nonpathogenic virus. This virus acts as a vector to deliver just the genetic material for the protein of interest. In each case the viral vectors are stripped of any disease-causing genes and sometimes also the genes allowing the virus to replicate.

Depending on the latter step, there are two types of viral vectors used. The non-replicating ones are unable to make new particles when they infect their target cells. Their role is simply to introduce the genetic material for the viral protein in question. Replicating viruses are also able to use the target cell’s machinery to produce additional viral vectors containing the genetic material of interest which can then go on to infect further cells, amplifying the level of production of the viral protein in question.

These types of vaccine are harder to produce on a large scale than the others, due to the need to produce large amounts of virus. Again, they are relatively new as a class, although previous human vaccines in this class had been approved (for example the Ervebo Ebola vaccine). The Oxford-AstraZeneca COVID-19 vaccine is an example of this type of vaccine, using an adenovirus (the common cold virus) as the vector.

But how do these vaccines take the leap from laboratory to hospital floor?

The regulatory questions

Under EU law, most COVID-19 vaccines in the EU must be approved under the centralised procedure, which is mandatory for any vaccine using biotechnology. These centralised marketing authorisations can only be granted by the European Commission upon favourable opinion of the EMA’s Committee for Medicinal Products for Human Use (CHMP).

Vaccine development for COVID-19 vaccines is being fast-tracked globally, and the EU is no exception. The EMA created the COVID-19 Task Force (ETF) to support the Member States and the European Commission (EC) in taking rapid and coordinated regulatory action on the development, authorisation and safety monitoring of treatments and vaccines for COVID-19. Amongst other things the ETF reviews scientific data on potential COVID-19 medicinal products, engages with developers in preliminary discussions, offers scientific support to facilitate clinical trials conducted in the EU, provides feedback on development plans of COVID-19 medicines and advises the CHMP and the Pharmacovigilance Risk Assessment Committee. Importantly, it also ensures close cooperation with stakeholders and relevant European and international organisations.

To accomplish the above, rapid procedures have been established and are available for products intended for the prevention or treatment of COVID-19. In this framework, rapid scientific advice is provided in support of the generation of evidence for treatments and vaccines for COVID-19. It is an ad hoc procedure which follows the general principles of the regular scientific advice, but with adaptations to facilitate acceleration. This includes no pre-specified submission deadlines for developers to submit their submission dossier, flexibility regarding the type and extent of the briefing dossier (to be discussed on a case-by-case basis) and a reduction of the total review timelines from 40/70 to 20 days.

A rapid agreement of a paediatric investigation plan (PIP) and rapid compliance check is also in place for COVID-19 medicines. This means that applications for agreement of PIP, deferrals or waivers for treatments and vaccines for COVID-19 are reviewed in expedited manner, with a total evaluation time for a PIP (including waiver or deferral) of minimum 20 days, compared to the normal timeline of up to 120 days of active review. The compliance checks will also be expedited.

Rolling Review is an ad hoc procedure used in an emergency context to allow EMA to continuously assess the data, as they become available, for an upcoming highly promising application. There can be several Rolling Review cycles, with each cycle normally requiring a two-week review, depending on amount of data, with responses to list of questions from previous Rolling Review cycles to be incorporated into subsequent Rolling Review submissions.

The CHMP has recommended the granting of conditional marketing authorisations for the vaccines that have been approved by the EC so far. This is not a new type of marketing authorisation, but one that has been in place for a number of years and is envisaged for medicines addressing an unmet medical need (which is the case with COVID-19, as there exists no satisfactory method of diagnosis, prevention or treatment authorised in the EU), and in emergency situations in response to public health threats recognised by the World Health Organisation or the EU.

The granting of this type of marketing authorisation with less comprehensive clinical data is justified provided that the benefit of the immediate availability on the market of the medicinal product concerned outweighs the risk inherent in the fact that additional data are still required.

A conditional marketing authorisation is different from an emergency use authorisation, which some countries like the UK and the US are using to permit the temporary use of an unauthorised medicine in an emergency situation while it lasts. Whereas an emergency use authorisation is not a marketing authorisation, a conditional marketing authorisation is a marketing authorisation with less comprehensive clinical data, which can be used provided that the benefit of the immediate availability on the market of the medicinal product concerned outweighs the risk inherent in the fact that additional data are still required.

The marketing authorisations granted are subject to some post-authorisation conditions, like the need to monitor the clinical trial participants for an additional period of two years, to ensure that a full dataset will be available at some point for these medicinal products.

Happily, with the rollout of vaccines well underway, the COVID-19 pandemic at last appears to have an end date. And though we hope it should never come to it, the regulatory process to enable rapid rollout may yet provide a useful precedent when it comes to tackling the next global public health challenge.

Read the latest update: MHRA approves Janssen COVID-19 vaccine