Smashing down the barriers: Where are we at with Covid vaccines?

In the absence of a vaccine or a cure for a deadly disease, staying home in your bubble is what you do. The concept is not new - to the best of my knowledge, the last time we did this in New Zealand was for polio in the years before a vaccine came along. So, what can we expect for Covid-19?

Traditional vaccine approaches not a great fast-track option

Traditionally vaccines have been developed for established diseases that make a significant number of people sick, have lasting complications, and/or have a high fatality rate. Once the pathogen that causes the disease is identified vaccine discovery can begin, if funding is forthcoming. However, today we are dealing with what has previously been referred to as “Disease X”, an unknown disease that will come from an unknown somewhere and need a vaccine quickly to minimise loss of lives. If the Covid-19 pandemic had emerged even five years ago, the prospects of a vaccine in 12-18 months might have been a bit of a fantasy.

An example of the sort of timeline traditionally involved in vaccine development is the quest for a cervical cancer vaccine. The link between the human papillomavirus (HPV) and cervical cancer was made in the 1980s. In the early 1990s an approach to a possible vaccine was discovered and in early 2000s early phase human clinical trials commenced. Two vaccines successfully completed human trials in tens of thousands of people and were licensed for use in 2006-7. That’s about 25 years of effort at a cost of something with around nine zeros (each). The average time is 15-25-years and some vaccines still remain elusive (such as HIV).

All vaccines need testing in people before wider use

Normally, after animal testing, vaccines have to pass successfully through three key phases of clinical trials before they can be licensed for use.

Phase I to test dose strength and safety: Healthy volunteers step up and receive the first doses of vaccine, usually in varying strengths (dose ranging). Safety and immune response are studied intensely. It is usually about a year from the first dose to last blood draw.

Phase II to test immune response in more people and safety: This usually involves hundreds of volunteers. Safety is studied in more people, and immune responses monitored. Usually the numbers are too small to see if the vaccine is effective against disease but if disease endpoints are included it could be about three years from first dose to last follow-up.

Phase III to test efficacy and safety: Phase III has two key functions. First, safety in even more people, and second, effectiveness at preventing the disease or some other endpoint such as infection. These studies are randomised trials where participants receive either the vaccine, a placebo, or another unrelated vaccine. Many modern vaccine trials will have tens of thousands of people in Phase III (e.g., HPV and rotavirus). Could be a year of recruitment and three-years follow-up, might overlap with Phase II.

These trials are essential in order for a vaccine to be licensed. As you can see, testing a vaccine in humans could be a 5-7 year process and is often a 10-15-year process all up, most trials experience delays along the way. There is also a Phase IV, but this is after licensure, will discuss that at a later time.

Breaking the first barrier to getting a vaccine through human testing

Clearly this a lengthy and expensive process and ineffective in a pandemic situation. It's also not attractive to a pharmaceutical company - even Big Pharma doesn’t have that much money to flush on a futile exercise!

The 2014-2016 Ebola outbreak in West Africa changed this paradigm. Prior to this Ebola vaccines had actually been developed then shelved, as the disease disappeared. When this Ebola outbreak struck, the first of the vaccine candidates came off the shelf and into Phase I trials that commenced a few months into the outbreak. While these early trials were underway, planning for Phase III began. Phase III commenced a year into the outbreak, but then Ebola went away again. Progress in this space was facilitated by Gavi (previously the Global Alliance for Vaccines Initiative), who encouraged and funded development and procurement for Africa. The regulatory agencies also stepped up. It became evident that under emergency conditions clinical testing can be expedited.

This expedited process is nicely depicted in a recent offering from the New England Journal of Medicine.

We now have an urgency for a Covid-19 vaccine. Given the learnings from Ebola, SARS and MERS, the Phase I trials for the first vaccine cab off the rank are running alongside the animal testing.

Traditional vaccine technology

Another barrier to producing a vaccine candidate for a yet-unknown disease practically overnight has been limitations in technology. To appreciate where the new technology is going, I have listed the traditional methods with examples of limitations below:

1. Live but weakened (attenuated) version of the pathogen: These induce excellent immunity without causing disease. There can be concerns about using in people with compromised immune systems, so not everyone can receive live vaccines. Another drawback is that you have to grow and process the virus or bacteria to make the vaccines.
   Examples: Measles/mumps/rubella (MMR) vaccines and rotavirus vaccines
   
2. Dead or inactivated pathogen: In the case of viruses, this means disrupting the virus ‘coat’ and removing most of the genetic material from inside. You still have to grow and process the pathogen. These vaccines are generally not as good as provoking immune response as live vaccines.
   Examples: Most seasonal flu vaccines
   
3. Sub-unit vaccines: These contain either a fragment or purified fragments of the pathogen, individual proteins produced by genetic engineering, or inactivated toxins (toxoid). Many different approaches are used and sub-unit vaccines can be lengthy to produce with multiple stages, often needing immune enhancers (adjuvants) to be effective. Examples: Tetanus, whooping cough, meningococcal.
   
4. Nanoparticle vaccines: These are newer on the scene. They could be thought of as sub-unit vaccines for simplicity. Nanoparticle vaccines may be self-assembling virus-like particles as in the case of HPV vaccines. I am inclined to put the vaccines below that use nanoparticles as delivery systems in this category too. There are loads of approaches with a few mentions below.

Newer concepts include the development of viral templates and RNA vaccines. These effectively allow us to ‘dial-a-vaccine’. But this needed more investment and focus on innovation.

CEPI

The Coalition for Epidemic Preparedness and Innovation (CEPI) was founded in 2017 by the governments of Norway and India, The Wellcome Trust, The Bill and Melinda Gates Foundation, and the World Economic Forum to break down the barriers outlined above – from technology to testing.

In the last couple of years CEPI have invested in innovative new technologies and the development of systems and services related to vaccine testing and deployment. Of particular relevance to Covid-19, they have invested in vaccine delivery platforms such as those mentioned above. They had a goal of a 16-week turnaround from the identification of a new pathogen to vaccine candidate ready for human testing. This has been achieved for Covid-19 in 45-days!

Viral templates

What are viral templates? Viral templates use an existing virus that is very well understood as a vector to get the gene of interest delivered to the target cells in our bodies, like a mock infection. A little piece of the DNA is removed from the vector virus and replaced with a piece from the pathogen of interest. This will usually be the gene that encodes for a protein that stimulates protective immunity. Examples of this are the Ebola vaccine rVSV-ZEBOV (Ervebo) and the Dengue Fever vaccine Dengvaxia. Such vaccines can induce nice immune responses.

Disadvantages to viral templates: One disadvantage is that if you develop an immune response against the actual viral vector it will be rendered useless for a second dose because the immune system would inactivate it. Another disadvantage is you need to grow the vaccine in cells, so more complex manufacturing is required.

Nucleic acid vaccines – using the code for life to get our own bodies to make the vaccine

What are nucleic acids? Deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) carry the instructions for life, for all organisms as well as viruses, even though viruses are not actually alive. Basically, these nucleic acids are like the detailed blueprint for a car that can be entered into a 3-D printer for production. DNA is the master code and RNA like a carbon copy that is carried to the machinery that makes proteins. Most vaccines are protein-based so hopefully you can see where this is going. We can get our own cells to make vaccines.

Advantages to nucleic acid vaccines: These approaches do not require growing highly pathogenic organisms at a large scale, which is much safer and more efficient.

mRNA vaccines

What are mRNA vaccines? RNA vaccines remove some of the challenges associated with DNA vaccines, including the hypothetical concern about host integration. Using this approach, we go directly to translating and producing the protein of interest that then stimulates the desired immune response. The reason the body recognises this protein as something to get rid of is because viral genetic material contains special features that animals have evolved to recognise as dangerous. These are called pathogen-association molecular patterns, or PAMPS.

Advantages of mRNA vaccines: You cannot make a virus out of this bit of RNA - that would be like assembling a car having only the instruction for the gearbox. Without the growth of highly pathogenic organisms at a large scale and less risk from contamination with live infectious reagents and the release of dangerous pathogens, this is a very attractive approach if you want something fast and at scale. Like DNA vaccines, RNA vaccines can be synthetically produced.

Covid-19 vaccines – some frontrunner examples

One of the vaccines backed by CEPI is an mRNA vaccine developed by biotech company Moderna in Massachusetts. They managed to produce vials of their vaccine for approval about four weeks after China published the virus genome. This was the first vaccine to be administered to humans, a few weeks ago now.

Other vaccines

As of 20 March 2020 there were 44 Covid-19 vaccine candidates. As well as the Moderna vaccine, there is a viral vector vaccine now in human trials. This vaccine uses an adenovirus vector (virus that can infect human respiratory cells) that has the gene for the spike protein of the Covid-19 virus inserted. This approach has previously been used for Ebola vaccines. CanSino Biological Inc. with Beijing Institute of Biotechnology China is the first to get one of these into human trials. The Moderna and CanSina vaccines are the first into humans.

How long before a vaccine is available?

The estimates continue to be around 12-18 months. This assumes that some of these early horses away from the starting posts make it to the finish line with minimal delays. It does not mean that there will vaccine available for everyone on the planet by then because upscaling, technology transfers, building facilities…. all takes time. But then again, China built a hospital in 10 days - anything seems possible when we throw everything at it!

I hope that the technology for successful vaccines will be shared immediately allowing multiple facilities globally to manufacture.

Who will receive the vaccine/s?

Vaccine deployment will ideally be prioritised.

Because the available number of doses of vaccine will initially be limited, it will ideally be directed to priority groups first. These will likely be:

• Frontline health care workers
  
• Persons at high risk of complications
  
• Countries/locations that have no way to isolate people that are experiencing the worst mortality

Limited vaccines can also be used to ‘ring fence’ where there are outbreaks to break the chain of transmission.

Never before has there been so much action in the vaccine space. Our job is to flatten the curve and buy time while the scientists get us a vaccine.