Covid-19 vaccine: The holy grail of medical researchers


THERE are two ways to become immune to an infection. One through the natural process of catching the bug, building immunity where antibodies, or proteins are produced that help our bodies fight the illness.

Antony Mutamba
surgeon

The other is by weaponising our immune systems by using a vaccine, which imitate the virus, prompting our bodies to create the same antibodies it would need to fight a full-blown version of that illness. The key ingredient of a vaccine is a weakened version or parts of the very virus it has been created to prevent.
The life-saving nature of vaccines has led people to ask when a vaccine against Covid-19, will be available. The answer is complicated, due to the steps involved to ensure patients’ safety, vaccine effectiveness, to mass production and the logistics of global delivery. With a public health emergency like Covid-19 some of the traditional steps in vaccine development have been précised.

It is important to develop a vaccine during an epidemic, in order to test the vaccine against the infection, and vaccine makers are often incentivised to move faster in the face of epidemics like Covid-19 for the payoff for success can be enormous. The development of a vaccine is generally in two categories:

Pre-clinical development

The exploratory phase is the research-intensive phase of vaccine development and is designed to identify an antigen (either weakened strains of a particular virus, or its parts), which when administered, causes the human being to develop protective antibodies against the harmful virus. This research is carried out in lab assays and animals. Traditionally antigens have consisted of a weakened form of the virus, that does not cause illness; but elicits production of protective antibodies (for example, measles, mumps, polio).

Newer technology has allowed creation of a vaccine that is not made from the weakened virus at all, but instead from part of a copied genetic code from the virus. However, no vaccine that has been made in this novel way has been approved thus far, with two undergoing human trials against Covid-19. Central to life is the human cell, which contains a highly protected sac within it (nucleus), that in turn contains DNA (the master blueprint that directs the activity of the cell, whether at multiplying or developing proteins and other substances essential for life).

Following a signal from the DNA, a form of a messenger, called mRNA (a copy of a fragment of the part of the DNA involved) is produced within the nucleus, a process called transcription. The mRNA migrates outside of the nucleus into the fluid within the cell, and its message is used (translated) to carry out the chore intended by the DNA, usually the production of a protein which then leaves the cell to carry out its functions.

Creation of the vaccine concept is as follows: RNA vaccines work by using a replicated part of the virus’ RNA — a set of its biological instructions, similar to DNA which is injected into a person, where it enters a cell and makes the cell produce proteins, which have some of the features that would be produced if the harmful virus had entered it.

The proteins, which do not attack the body like those produced by the virus, are tackled by the body’s immune system and the fight is remembered for future defence. RNA vaccines have produced promising results in flu vaccines.

DNA vaccines work by injecting a harmless part of a virus’ DNA called a plasmid into the body, which is then absorbed by the type of cell that makes proteins. In a similar way to the RNA vaccine, the body’s defences recognise the proteins as foreign and attack them.

Because the body is familiar with fighting the protein, if the real virus enters later, the proteins it produces will be remembered and the virus destroyed. Yet another type of fairly new vaccine, called a viral vector, is also promising. It works by combining the structure of a harmless virus (genetically programmed not to reproduce) with a portion of the DNA of the virus the vaccine is meant to protect against. The body creates antibodies against both the harmless virus and against the DNA of the harmful virus, so that when the real virus enters the body later, it is able to defend itself. This has been done successfully to tackle Ebola. Most of the vaccines under development for coronavirus, though, are of an already established type called protein sub-unit.
This works by using a protein that makes up only part of the virus — the sub-unit. This can be a protein that makes up part of the virus’ surface. The body defends itself against the harmless protein and remembers it if the real virus enters the body in the future. Working examples are hepatitis B and human papillomavirus (HPV).

Pre-clinical phase is research carried out on animals. The drug has to be put into animals to see if their immune system responds. The animal has to be able to react in a sufficiently similar way to how a human would, and it has to be capable of being infected with the disease that is being vaccinated against.
Some of the tests may show the vaccine to be toxic to animals, and will probably therefore be so in humans. Other vaccines may largely skip the animal testing phase because they are a new version of a vaccine which is already widely used, and therefore its toxicity is well known. The aim of the tests is to work out which candidates can go on to further trials.

The vaccine is now ready for production; meaning getting it to the stage where is can be given to humans, and assessing whether it can be mass produced. Once scientists have created a potential vaccine, they have to work out whether it can be practically used in the real world.

Clinical development

This is when the vaccine is first tested in humans. Rigorous ethical principles of informed consent from volunteers, with emphasis on vaccine safety as well as efficacy, are applied. Once clinical trials are approved, the vaccine must pass three trial stages of human testing: Phase I administers the candidate vaccine to a small group (less than 100 people) with the goal of determining whether the candidate vaccine is safe, and elicits the production of antibodies.
Phase II, which includes hundreds of human test subjects, aims to deliver more information about safety, determining whether it protects against the virus, immunisation schedule and dose size.

Phase III, which can include thousands or tens of thousands of tests subjects, continues to measure the safety (rare side effects sometimes do not appear in smaller groups) and effectiveness of the candidate vaccine.

After Phase III, the virus is licenced for clinical use. The final Phase IV happens after the vaccine has been licensed and introduced into use. Also called post-marketing surveillance, this stage aims to detect rare adverse effects as well as to assess long term efficacy. There are also logistical considerations, such as the cost of the vaccine, distribution, establishment of satellite manufacturing plants etc.

Current state with Covid-19

Most scientists agree that it is likely to take 12 to 18 months; a record pace given that most vaccines can take up to 10 years to come into clinical practice. This is because we have a head start. Two previous pandemics involving coronaviruses; the severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) occurred in the last 20 years, reinforcing the need for potential vaccines.

One of the reasons that we may be able to achieve such a target is because Covid-19 is part of the coronavirus group, for which a lot of study and research has already been done. The groundwork for vaccinations against SARS and MERS was laid during their outbreaks, but once the spread had been contained, this was then stopped. The genetic sequencing of Covid-19, is already known, making it easier to create vaccine.

Even if a candidate vaccine proves successful during trials, one of the reasons it may still not be adopted and rolled out widely is because it cannot be easily and quickly manufactured.

The biggest difficulty, is making sure the vaccine that has been produced in relatively small amounts in the lab, can be mass produced so that millions of doses can be distributed easily in the field. During the response to the devastating Ebola crisis in West Africa, while pharmaceutical companies have extensive experience of this, the economics and practicality of vaccine development and large-scale manufacture prevented a number of potentially effective vaccines coming on to the market – with many said to cost up to US$1bn to bring to the market.

All the current vaccines we have (polio, measles, papillomavirus etc), are very different. There is no generic process to make them. There is a dedicated factory, a dedicated process, very different technologies for each vaccine. Vaccines are grown, they are not manufactured by a factory. Very important it is that the tested vaccine that you test is to the brewed one; the easy bit at the end is putting it into syringes for distribution.

What RNA and DNA antigens offer is an escape from that laborious brewing process. We can make the RNA by a single process in a single factory. All we have to do is change the sequence of the RNA or DNA, depending on the genetic material of the antigen. RNA and DNA vaccines trials have been promising and many scientists believe it could be one of those two types that will be the model that goes into mass production against Covid-19. The attraction, is that they will potentially offer a step towards something that has been the holy grail of vaccine design — the universal vaccine.

A possible model for vaccine development in times of crisis was laid down in West Africa during the Ebola crisis when the process of vaccine testing and adoption was accelerated due to the urgent need for a drug to protect people. Several were trialled in the field — while the outbreak was ravaging countries and it led to several generating results. One of those vaccines has since been licensed and the other is undergoing further trials in the Democratic Republic of the Congo. In Ebola, the first trials in outbreaks were running in 16 weeks, with Covid-19, they have been set up within three weeks. Given the desperate rush to produce a cure, at times Phases I and II clinical trials can run concurrently.

Five leading candidates for the development of a Covid-19 vaccine are two in the US, two in the UK and one in China and they have started human trials; with more than 67 in the pre-clinical phase prior to human trials.

Mutamba is a UK-based ophthalmic and oculoplastics surgeon, with a passionate interest in Zimbabwe.

He works as a consultant in the UK. His credentials are as follows: BSc Hons (UZ), MBChB Hons (UZ), MSc (Lon), DTM&H (Lon), MRCP (UK), FRCOphth (UK).