Training our body’s SWAT team to fight COVID-19: what’s in a vaccine?

As world leaders discuss exit strategies from the current pandemic-induced lockdown, scientists warn that the much-anticipated vaccine remains in early stages of development. Since obtaining the genetic sequence of the SARS-CoV-2 virus, which is known to cause COVID-19, scientists all over the world have worked to develop 100+ vaccine candidates, five of which have now entered first-in-human (Phase I) trials [1]. The current leading candidates are summarised here.

Since the principle of vaccination was first demonstrated by Edward Jenner in 1798, global outbreaks of several, life-threatening diseases, including measles, polio and tetanus have been prevented by development of a vaccine, or immunization. Immunization aims to prime the immune response to a specific pathogen, a disease-causing organism. Interestingly, the word “vaccine” originated from the Latin term, ‘vacca’ meaning ‘cow’, after Jenner successfully demonstrated that injecting, or inoculating, a person with cowpox virus could protect the individual from smallpox.

Whilst some modern vaccines are a weakened, or attenuated, version of the original invader, or pathogen, scientists have since uncovered several other approaches to develop novel vaccines including:

Direct injection of a pathogen’s genetic material in the host’s blood stream (DNA or mRNA vaccines) (Figure 1)
A genetically modified, non-disease-causing virus that contains viral DNA (Viral vector vaccine) (Figure 2)

Both of these approaches have produced COVID-19 vaccines that have entered Phase I clinical trials [1].

When fighting a viral infection, our immune cells destroy infected cells to prevent viral replication and survival. A vaccine works by imitating an infection, causing the body to respond as if it has been exposed to the disease-causing virus. Two types of white blood cell, or lymphocyte, are key to our body’s advanced, or adaptive, immune defence: B cells produce antibodies, which work as a natural ‘police squad’ and help recruit T cells, which act as a ‘SWAT’ team to remove the invading virus. Antibodies prevent the entry of viral particles into target cells, such as those lining our airway in the case of COVID-19. Both B cells and T cells recognition ‘warning flags’ on the surface of ill cells which are made from small pieces of the virus. Fortunately, our immune system is also able to memorise how it responds to a mock invasion through another subtype of B cells, known as memory cells. Zania Stamataki, a viral immunologist at the University of Birmingham explains how “vaccines prepared using harmless parts of the virus can help us build protective memory” [2] and prevent future outbreaks.

Vaccines and the development of Herd Immunity – Presented by the Microbiology Society, narrated by Dr Adam Kucharski, who is an Assistant Professor of Epidemiology at the London School of Hygiene and Tropical Medicine

The world’s first human studies to test a vaccine against COVID-19 began on the 16^th March 2020. The vaccine candidate, known as mRNA-1273, was created by US-based scientists at Moderna, who developed an RNA vaccine which can produce the well-characterised spike (‘S’) protein, used by the virus to enter human cells. A similar approach has been used a research team led by Professor Shattock at Imperial College team, London, who have recently shown their vaccine candidate to be effective in mice, producing antibodies against SARS-CoV-2. When a virus is unable to enter the host cells, it cannot replicate and instead is more visible to attack by the immune system. Given its success in animals, the team hope to begin clinical trials of this vaccine in June, this year, following extensive recruitment of volunteers [3, 4].

Both teams have engineered an additional genetic sequence onto the mRNA molecule to allow it to ‘self-amplify’ inside our body. This allows doctors to administer a lower dose of vaccine without compromising effectiveness. When the vaccine is injected into the muscle, the cells take up the mRNA and process it further to create a ‘flag’. This stimulates a specific, highly-effective immune response, which will only re-occur if the individual is subsequently infected with a virus expressing an identical ‘S’ protein.

Figure 1 **The structure of an mRNA vaccine** The genetic sequence that codes for the viral *spike* protein (‘S’) is encased in a double membrane, or *bilayer* of fat cells, or *lipid*s. Scientists design the genetic sequence to be ‘self-replicating’ by ‘stitching’ a second genetic sequence to the messenger molecule.

Another UK-based research team, led by Professor Sarah Gilbert at the Jenner Institute, University of Oxford, in collaboration with the Oxford Vaccine Group, have received £20 million in government funding to develop a second vaccine candidate, using a different approach, one that involves a viral vector. In this case, that genetic information encoding the ‘S’ protein is delivered to host cells by an attenuated, or weakened, version of a chimpanzee adenovirus, a family of viruses known to cause the common cold in humans [5,6]. Oxford’s vaccine candidate is called ChAdOx1 nCoV-19 and has been modified to prevent disease in humans. Several studies have shown that modified adenoviruses are safe and well-tolerated as therapeutic delivery systems for vaccines against infectious disease and cancer. A similar approach is currently being used by researchers in Belgium and China, using different adenoviruses (Ad26, Ad5)[7]. One major benefit of this approach is that viral vector vaccines are known to mount string immune responses in humans and have already been developed to tackle other viral infections including Ebola and HIV.

Figure 2 **How a viral vector vaccine works** A modified *adenovirus* is used to deliver the genetic information encoding the viral *spike* protein to host cells. The machinery within the host cell translates this genetic information to produce *spike* molecule, or *protein* which acts as a ‘flag’ to our immune cells. B cells are able to recognise this flag and produce *antibodies* that will help fight the infection. In addition, our body is able to memorise this immune response therefore providing better protection against future invasion by the same *pathogen*.

Whilst several vaccine candidates have already entered clinical trials, Stéphane Bancel, Moderna CEO, tells The Scientist that “nobody knows which vaccines are going to work.”

Traditionally, the development of a new medical treatment is a multi-stage process, starting with thousands of candidates before only one lead therapy is brought into clinical trial. Scientists acknowledge that a traditional approach would not be suitable to tackle the current pandemic, however in the absence of any definitive treatment options for COVID-19, clinical trial design has had to adapt fast. Recent studies involve highly-regulated human challenge trials, the outcome of which will be essential to ensure the safety of any of new vaccine candidate. Challenge trials have two stages; a pre-determined dose of the candidate vaccine is first administered at a pre-determined interval, followed by a challenge phase, in which the individual is artificially infected with a known amount (viral titre) of SARS-CoV-2 [8]. These studies are performed on young healthy volunteers who are otherwise at low-risk of experiencing severe symptoms of COVID-19. Volunteers remain isolated and are closely monitored throughout the duration the study with priority access to clinical treatment, if required. It is only once the vaccine formula has been evaluated as safe and successful, that the experimental vaccine will be trialled in the target population, or the individuals who are at a higher risk of developing COVID-19. No challenge phase will be involved in later phase trials.

Arguably, the biggest challenge in managing the spread of COVID-19 is that our knowledge concerning key aspects of viral biology of SARS-CoV-2 remains in its infancy. One major concern with regard to vaccine development is that scientists do not know whether our immune system can generate long-term responses to this coronavirus. Efficient vaccination may require multiple doses at time intervals such as 3-, 6- or 12 months after the initial vaccination.

When discussing exit strategies from the current lockdown, Mark Woolhouse, an epidemiologist at the University of Edinburgh commented that “waiting for a vaccine should be dignified with the word ‘strategy’. It’s not a strategy, it’s a hope,” talking to New Scientist.

Beyond vaccine research, scientists have been working to upscale COVID-19 testing facilities and develop infrastructure to increase manufacturing capacity, in preparation for when a suitable vaccine may become available. Public health experts explain that any new vaccine/treatment must be delivered to the global population at the same time, irrespective of financial/social/geographical circumstance. As a scientist myself, it’s incredible to witness the vast extent of collaboration between industry, academic research and non-medical disciplines alike. Richard Hatchett, chief executive officer of the Coalition for Epidemic Preparedness Innovations (CEPI), commented that “(humanity) really can’t deal with this (pandemic) one country at a time” and therefore it’s important continue to look after ourselves and those around us – particularly as our body’s own immune system remains the best fighter in this microscopic war.

Featured Photo by National Cancer Institute on Unsplash

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