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

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