As recently as six months ago, naysayers were warning, “We may never have a vaccine against Covid-19”. Yet a year after SARS-Cov-2 emerged, the first vaccine programs are already rolling out in the US, the UK, India, China, Israel, Chile, Indonesia and many other countries. Israel has already vaccinated more than 20% of its population within one month of commencing, and is seeing a dramatic impact on infection rates. Australia has flagged commencing vaccinations in the coming weeks, with early jabs from mid-February ahead of a wider drive in March.
Extraordinary vaccine development
The year 2020 saw an extraordinary global effort in expedited vaccine development, while still subjecting these vaccines to the usual regulatory hurdles. There are more than 60 vaccines in clinical development and over 170 in pre-clinical development, which is very good news for the world. Some, such as the vaccines being developed by Merck and the University of Queensland, have dropped out of the race, but that is to be expected in vaccine development. Normally, vaccine development takes many years, or even decades, and dropouts are expected along the way.
There are three basic technologies being used – whole virus (killed or attenuated), protein (using a key protein from the surface of the virus) and vectored vaccines (which deliver genetic code or protein piggybacked onto a harmless other virus). These three methods are tried and tested old technology, especially whole virus and protein subunit vaccines. A further breakthrough technology are the new RNA vaccines (typically referred to as mRNA), in which the genetic code for the protein that elicits an immune response is injected into the body. All aim to trigger a protective immune response against the virus. Many vaccines, including some Covid-19 vaccines, generate more robust immunity than natural infection.
In Australia, we have contracts for AstraZeneca (a vectored vaccine), Pfizer (a mRNA vaccine) and Novavax (a protein vaccine). We are also fortunate to have domestic vaccine manufacturing capacity at CSL in Melbourne, which will manufacture the AstraZeneca vaccine under license, thereby avoiding supply-chain problems which may occur when procuring directly from overseas. In a pandemic, having domestic manufacturing capacity is a huge advantage. CSL is also technically able to manufacture Novavax, but is not set up to manufacture mRNA vaccines.
The knowns and the unknowns
At this stage, only three vaccines have had phase 3 clinical trials published. These are the final data required to assess a vaccine, which show the efficacy of the vaccines against disease in humans, usually compared to a placebo or other (non-Covid) vaccine. These are the vaccines by Oxford-AstraZeneca (a vaccine vectored on a non-replicating chimpanzee adenovirus), Pfizer/BioNTech (mRNA vaccine) and Moderna (mRNA vaccine). We can directly compare the one endpoint that all three trials reported on – protection against symptomatic infection.
The best by far are Pfizer (95%) and Moderna (94%), both of which require two doses given three weeks apart, with AstraZeneca substantially lower at 62% after two doses. An accidental reduced dose schedule in the AstraZeneca trial provided data suggesting giving a low dose followed by standard dose may improve efficacy to 90%, but this requires confirmation in a further clinical trial, and there are suggestions the effect was due to spacing the doses further apart (three months instead of four weeks). All vaccines were close to 100% effective in preventing death and serious disease.
What we do not know yet is the efficacy of these vaccines in preventing all infection (symptomatic and asymptomatic). This is of interest in assessing the ability to achieve herd immunity. Only AstraZeneca has published data on asymptomatic infection, and the vaccine is not very effective on that front. Data presented to the US Food and Drug Administration for the Moderna vaccine suggests it is quite good at preventing asymptomatic infection.
The only complete exit strategy is a vaccine with high enough efficacy to achieve herd immunity and eliminate the virus.
We also do not know the duration of efficacy of these vaccines, which like the protective efficacy will probably vary. Some vaccines, such as measles, give lifelong immunity, but others, such as whooping cough, have waning immunity over time. It is likely coronavirus vaccines will have waning immunity, which may be addressed with booster doses – we do not yet have long enough follow-up data to know the duration of efficacy and when a booster may be needed.
We will have many more vaccines becoming available over time, and some will be better than others. Unpublished reports of efficacy for whole killed virus vaccines by Sinovac is 50%, and Sinopharm, 79–86%; for the Sputnik vectored vaccine, 92%; and for the Novavax protein vaccine 89% in the UK, but only 60% against the South African mutant. . If Australia were to consider adopting any of these vaccines, these would need to be assessed under regulatory protocols including published phase 3 clinical trials. We do not know the efficacy of the AstraZeneca vaccine against the mutant strains. The standout so far seems to be the mRNA vaccines.
Vaccines as an exit strategy?
The pandemic today is much worse than it was even six months ago, so the risk of infections coming into the country through breaches in hotel quarantine is high. If any of the highly contagious mutant strains arising in the UK, Brazil or South Africa is introduced into the community, controlling the outbreak will be much harder. There are some suggestions that current vaccines may not be as protective against South African and Brazilian mutants. If this becomes a problem, vaccines can be revised to match these strains, but Moderna reports good protection against the UK and South African mutants.
The majority of the Australian population is non-immune to the virus, so we will remain vulnerable to outbreaks until we can vaccinate enough of the population to achieve herd immunity, or at least protection from death and severe disease. Until that time, we will live with that risk and with a level of restrictions which impede complete economic recovery.
The government has stated that herd immunity is the ultimate goal. Herd immunity occurs when enough of the population is immune to protect everyone, including unvaccinated people, from community transmission. For that, we need a vaccine of at least 80–90% efficacy against infection and about 70% of the population vaccinated. Herd immunity cannot be achieved through natural infection. In the pre-vaccine era, no infection controlled itself through herd immunity – not smallpox, measles or any epidemic infection. They caused ongoing, massive epidemics, over and over, until vaccines were used.
The only complete exit strategy is a vaccine with high enough efficacy to achieve herd immunity and eliminate the virus. Initially, children will not be vaccinated, because clinical trial data in kids under 12 years are not yet available. This means herd immunity is still possible if a very high proportion of adults are vaccinated with a high efficacy vaccine. But the task will be easier once kids can also be vaccinated.
It is unlikely that lower efficacy vaccines will be able to achieve herd immunity, but they will reduce the risk of death and serious illness. However, someone vaccinated with a lower efficacy vaccine may still get infected, and this has implications for the opening up of society. A vaccine which cannot achieve herd immunity will result in SARS-Cov-2 circulating long-term and continuing the risk of outbreaks.
The choice of vaccine will have implications for international travel. The idea of immunity passports showing evidence of vaccination is not without precedent, as this already occurs for Yellow Fever. However, the type of vaccine received may result in a different stamp on the immunity passport. Someone vaccinated with a lower efficacy vaccine could travel, get infected and bring that infection back into the country, so might get a different risk assessment to someone who receives a high-efficacy vaccine. Airlines too may assess passengers differently based on which vaccine they have received.
Where to from here?
In the immediate future, we will need to keep using restrictions and non-pharmaceutical measures to control outbreaks, which will also impact on societal and economic recovery. Careful and strategic decisions about vaccines matter, and diversifying our options with more agreements with different manufacturers will help, so that we can rapidly pivot if the need arises.
Vaccine development is an uncertain game, and the UQ vaccine may not be the only one in our portfolio to not be realised. Further, as new vaccines come out, there will continue to be wide variation in efficacy and safety, so having many options will keep us better protected. We already know the efficacy of vaccines may be less than the new mutant strains, so we need vaccines that can protect against these.
Herd immunity remains possible, given the promising early data on the mRNA vaccines, and if any country can achieve this, it is Australia – we have an enviable record of very high vaccination rates for our National Immunisation Program.
We should also consider investing in domestic manufacturing capacity for mRNA vaccines, as this revolutionary technology is likely to expand in the future, including to development of new drugs and treatments for many diseases. Australia would be well served if we have this capacity.