Analysis: what's going on with the search for a vaccine - and what does Ireland need to do to increase its research in this area?

The endgame to the Covid-19 pandemic needs the identification and manufacture of a safe and effective vaccine and a subsequent global immunisation campaign. Mass deployment of a safe and effective vaccine will initially induce herd immunity and should aim to eventually eradicate the virus from the planet.

What's involved with tests for a vaccine?

Multiple vaccine platforms are being developed to address this need. All vaccines consist of, at least, SARS-CoV2 protein antigens or the genetic material that acts as the blueprint in a cell to produce these antigens. These vaccine technologies, commonly termed "platforms", range from conventional, inactivated technologies to the most recently developed RNA vaccines.

An inactivated vaccine is the most traditional method of making a vaccine where a killed (inactive) version of the virus that causes Covid-19 is used. A number of companies and research institutes are taking this approach. Some have shown that their inactivated vaccine can induce antibodies in macaques. Although inactivated vaccines have a long proven safety and efficacy in human (e.g., inactivated polio vaccine) and veterinary health, one has to wonder if this inactivated SARS-CoV2 vaccine is feasible with respect to the stringent biosecurity requirements for large scale manufacturing. Human clinical trials, in time, will tell us about efficacy.

From RTÉ Radio 1's Today with Sarah McInerney, Dr Anne Moore on the search for a Covid-19 vaccine

To avoid these biosecurity measures, several companies are focussing on producing one protein antigen from the virus completely separately from the rest of the virus. These so-called subunit vaccines generally need an immune-modulator, called an adjuvant, to make these vaccines as potent as possible. This has resulted in several collaborations between the subunit protein manufacturer and an adjuvat producer. At least two subunit vaccines are in clinical testing at present.

Are there other methods to produce a vaccine?

At the opposite end of the vaccine innovation scale are nucleic acid-based platforms. These vaccines are completely synthetic; a strand of DNA or RNA that encodes a gene that expresses a protein of the virus (the antigen) is manufactured. Once injected, the DNA or RNA needs to get into a cell and the genetic instructions are read by the cell to produce this protein antigen.

Moderna were the first to clinically test their RNA-based vaccine, but no data has yet been published from their phase I clinical trial. Notably, Pfizer/BioNTech published results from their US-based clinical trial of their RNA vaccine at different doses. Their interim demonstrates that vaccinated volunteers had good functional antibody responses, termed neutralising antibodies, one week after a second immunisation. These RNA vaccines all differ in aspects of the composition and/or function of the RNA and of the formulation needed to protect and deliver the nucleic acid into a cell. Finally, Inovio Pharmaceuticals' DNA-based vaccine is in clinical testing.  

From RTÉ Radio 1's Morning Ireland, James McInerney from the University of Nottingham on the world laboratory collaboration on a treatment for Covid-19

The traditional issues with these vaccines is the need to maximise the amount of DNA or RNA that successfully gets into the cell. If only a small amount succeeds in this journey then only a small amount of antigen is produced and this may not induce strong enough immune responses. One potential issue for nucleic acid vaccines, if they are successful in clinical trials, with respect to safety and efficacy, will be how to mass produce the final vaccine product at sufficient quantities for mass immunisation campaigns. This has never been done before. This raises a question about the security of supply chains for these materials.

What's the role of industry in all of this?

Virus vectors such as adenovirus are at the higher end of the innovation scale are virus vectors and the Jenner Institute at the University of Oxford are a leading academic institute in this area. They developed a vaccine, termed ChAdOx1 nCoV-19. It is made from a virus (ChAdOx1), which is a weakened version of a common cold virus (adenovirus) from chimpanzees that has been genetically changed so that it is impossible for it to grow in humans. This adenovirus is altered to prevent it from spreading in the body and also to produce the SARS-CoV2 spike protein.

A good safety profile of the ChAdOx1 platform has been demonstrated previously in other clinical trials, for example, for influenza virus and for another coronavirus, MERS. This pre-existing clinical knowledge on safety and immunity of this vaccine platform provides a good level of confidence for regulatory authorities with respect to its use in COVID-19 vaccine clinical trials. The University of Oxford have formed a strong partnership with AstraZeneca to prepare for very large-scale vaccine supply. This is a great example of academic research translating to large scale with the support of industry; the only mechanism of ensuring that a vaccine will be tested, licensed and distributed.

From Morning Ireland Extra, Cian McCormack looks at the science, manufacturing and ethics behind the development of a Covid-19 vaccine

How will these vaccines work?

All of these vaccines in clinical trial at the moment are injected into the body; the muscle or the skin. They aim to induce high immune responses in the blood and deep in the lungs. Results from macaque studies, for example with ChAdOx1-nCoV, showed that vaccinated animals had little to no virus in their lungs, though some virus was still present in the nose. These results are promising. If it works, then this vaccine should protect the immunised person from COVID-19 disease.

What research is being conducted in Ireland on a vaccine?

Many other vaccine technologies are also being developed to combat Covid-19. We collaborate with Vaxart, whose technology is based on administering the virus-vector based vaccine using a convenient room temperature-stable tablet, rather than by injection. They have demonstrated that their technology induces immunity in the blood and, significantly, also in mucosa; the linings of the nose and respiratory tract. If their Covid-19 vaccine is successful in humans, then this should protect the individual against disease and it might also protect the population against transmission of the virus. This tablet-based vaccine could enhance global vaccine deployment. 

In a complementary focus, we are also researching other injection-free vaccine systems, such as skin patches and other oral delivery systems. Current logistics costs, including cold chain and training, can double the cost of fully immunising an individual in some countries. This complicated and expensive distribution logistics and administration system will hamper national and global roll-out of a pandemic vaccine resulting in delayed and inequitable vaccine coverage.

From RTÉ Radio 1's The Business, Fionnuala Keane (Health Research Board) and Dr Philip Cruz (Glaxo Smith Kline) on the race between pharmaceutical companies to find a vaccine

Staff working in immunisation programmes will need to determine where they will store this new vaccine in addition to vaccines that are already in use. We developed an easy-to-administer, thermostable, needle-free skin patch, termed ImmuPatch for vaccination. These thermostability and operational advantages offer a solution to equitable vaccine access and enhanced vaccine coverage. This would have clear international public health benefits, if successful. We are currently further developing this technology for Covid-19 and seeking further funding to ensure that we can maximise our impact.

What are the hurdles and obstacles ahead?

Despite the accelerated progress to clinically testing multiple Covid-19 vaccines, there are still many fundamental scientific and logistic gaps and hurdles to reaching the endgame of deploying a safe and efficacious vaccine. For a start, we don’t know if they work and are relying on natural infection to give us this answer.

In the absence of an experimental challenge model, clinical trials are based on vaccinating large numbers of volunteers in the population with a Covid-19 vaccine or placebo vaccine. Then, we have to let nature take its course to determine how many vaccinated individuals are infected compared to the placebo volunteers.

Successful public health measures to decrease the number of infected people is a great triumph of current pandemic efforts, but it makes vaccine efficacy trials difficult. To overcome this problem, vaccine efficacy trials that need a fast answer need to take place where there are high levels of virus transmission; currently the United States, Brazil, Russia and India. If infection rates remain high then we will get an answer on vaccine efficacy sooner. If infection rates decrease globally and there is little circulating virus, then we cannot determine if a vaccine protects against infection that  is not present in the community.

From RTÉ Radio 1's Drivetime, Philip Boucher-Hayes reports on safety concerns surrounding vaccines

We don’t know what magnitude of immune responses will provide protection against infection and against disease. Do we need to maintain really high levels of circulating antibodies to ensure protection? Would the other half of the immune system, T cells, provide protection against infection? What level of immunity is good enough to protect vaccinated individuals? We don’t know.

However, substantial resources were put into structural immunology; identifying what is the best four dimensional conformation of similar coronavirus antigens to induce protective immunity. Due to this research, candidate antigens were known and could be produced in the correct shape, at the outset of this pandemic. This knowledge, along with significant previous research on vaccine technologies, ensured a rapid vaccine response to SARS-CoV2.

What is the durability of vaccine-induced immune responses? Will we need to seasonally boost people to provide protection? Again, we don’t know. We need to ultimately find a vaccine system that induces long-term protection but what if initial vaccines will only induce responses that are sufficiently strong for a few months? We just don’t know at the moment what "sufficiently strong" means. We can try to predict what will be protective, based on our understanding of immunity to other coronaviruses that seasonally circulate and cause the common cold and based on recovered Covid-19 patients.

There could also be constraints in manufacturing. How quickly can we manufacture billions of doses of a new vaccine? What impact will that have on the supply chain for other vaccines? Substantial effort is being put into ensuring that vaccine manufacturers can access every single material and resource that is needed to make this vaccine. This includes steel tanks to produce the vaccine, rubber stoppers to put on the vial and all the reagents needed to produce it and prove it has the requisite quality to be safe to be used in humans.

As always, the biggest resource needed is human capital. Vaccine manufacturers need skilled employees to work on producing vaccine as well as all of the legal, clinical and commercial aspects in this industry. In Ireland, we have a great tradition of high quality education in life sciences and many of our university graduates are driving the pharmaceutical sector forward, including in the area of testing and licensing new vaccines.

Once a safe vaccine has demonstrated sufficient safety and efficacy for it to be licensed, the next big issue is its deployment and equitable access. Global organisations, such as WHO and CEPI as well as national governments and the EU launched funding drives to financially support the development and deployment of vaccines and therapies. We are contributing to finding technical solutions to vaccine deployment.

Will multiple vaccines be needed?

Most people agree that multiple types of vaccine will likely be needed to combat Covid-19. It is possible that different vaccines will be used in the same person, termed heterologous prime-boost strategies. More than one company will likely be involved in providing these vaccines which requires strong agreements between the companies and between the companies and the healthcare providers. The good news is that there is precedence for this, as evidenced with Janssen and Bavarian Nordic's partnership to develop an efficacious Ebola virus vaccine. It can be done.

How important Is funding in this area?

The speed of the response by the vaccine field to this pandemic is unprecedented. Significant investment in research into emerging infectious diseases and into basic research that contributes to scientific understanding meant that we knew what the virus was quite quickly and we had the tools and technologies to start making vaccines.

But support for valuable research on human immunity to seasonal coronaviruses has been limited for many years and only a small number of researchers have continued to research human coronaviruses, resulting in a lack of knowledge on how humans respond to coronaviruses. Vaccines that induce only temporary protection will be good for an emergency response, but we need to commit to the long term and maintain the momentum of developing a vaccine for the endgame to this virus and to future pandemic threats. This commitment did not happen for previous pandemics such as Zika virus and SARS. How can we prevent this decreased interest and removal of funding for coronavirus and pandemic vaccine development?

What does Ireland need to improve its scientific research in this regard? 

In Ireland, the financial commitment to research is well below the OECD average. Without a commitment to supporting a culture of research into all facets of life, across the sciences and humanities, we are hampered in our collective ability to understand the world around us, to innovate, to be creative and to prepare and respond to emergencies. The successful response to this pandemic in Ireland can be partly attributed to the goodwill and generosity of scientists, researchers, clinical and other frontline staff, as well as the public to provide whatever it took to flatten the curve.

But we cannot expect this, by default, in the future. We need to build a sustainable culture of research and scientific research in this country. We have an excellent Agriculture and Food Development Authority (Teagasc), but lack a state-funded institute for human health research. Many of the accelerated developments in the UK and US can be at least partly attributed to the existence of and commitment to national institutes for health, such as the National Institute for Health Research (UK) and National Institutes of Health (US)

Professional scientific research careers should be possible in a state-supported or state-run health research institute and supported so that we have the expertise readily available to address future disease outbreaks as well as the next pandemic. As Mary Lasker said "if you think research is expensive, try disease". We as a society unfortunately now have proof of this statement.

The views expressed here are those of the author and do not represent or reflect the views of RTÉ

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