There are two big uncertainties with COVID-19. The first is whether there will be a vaccine and if so, when it will be rolled out. The second is the proportion of asymptomatic cases for each confirmed case. This second issue will have a fundamental influence on how long will it take, both with and without a vaccine, before some level of population immunity can be reached across the globe.
Despite the huge uncertainties in relation to both a vaccine and asymptomatic infections, there is newly emerging empirical evidence in relation to each of them. I will look at each in turn.
There are also some other issues where the evidence is now more sustained and increasingly compelling. First, it is increasingly likely that genuine elimination of the disease within New Zealand can be achieved and kept that way, as long as border control remains tight. Getting it wrong at the border risks everything.
Second, there is very high likelihood that Europe and the USA will have at least one more devastating wave of COVID-19, with that wave much more devastating than the current one. It is going to be a big mess.
Third, in much of the less-developed world, including middle-income countries such as Brazil, COVID-19 is out of control and unstoppable.
More on all of those also.
There is good news with vaccines
Just this last week, American-based Moderna announced early stage success with its revolutionary messenger RNA (mRNA) vaccine trials. Many in the global media, parroting off each other, misunderstood what it was about and provided a flawed commentary, including the mistake that results were based on only eight people.
But not everyone was fooled. The big investment companies had more analytical expertise at hand than did the media, and so global share markets jumped on the day of the announcement. Within the media, there is now debate as to whether that was insight or exuberance.
First some background. Currently there are no mRNA vaccines that have been licensed for any disease. This is because it is a revolutionary technology that Moderna, and no doubt some others, have been working on for quite some time trying to sort out the wrinkles. This started long before COVID-19 came along.
mRNA is the mechanism by which the body produces protein on command from DNA. It is the process that drives all protein synthesis. Depending on the message contained within the mRNA, cells can produce any protein. This includes proteins that are specific to coronaviruses but which by themselves have no ability to cause COVID-19 or any other disease.
Moderna has now worked out how to manufacture the right type of mRNA. More importantly, they have also worked out how to transport the mRNA through cell walls and to then keep it active. The human cells then synthesise the specific protein as commanded by the mRNA.
The body then reacts to this foreign protein by producing antibodies. In this way the body is primed to attack COVID-19 virus particles containing the same protein. At that point it is close to game over for COVID-19!
So how far has Moderna actually got? The first step was to inject the specific manufactured mRNA into 45 humans and see what happened. The first piece of good news was that none of the 45 people got seriously sick, although at the very highest dose, which was 18 times the low dose, some people did get a one-day fever. The second piece of good news was that all 45 people, including all of those at the low dose, produced the specific COVID-19 protein and everyone then produced antibodies. So that means that they only need to focus on the low and medium dose rate, and can forget about the high rate.
This antibody development stage is called ‘seroconversion’. The next stage is that antibodies were collected from the first eight people in the trial and these antibodies latched onto and destroyed COVID-19 in a test tube. In scientific language, they neutralised the virus. In the next few weeks, Moderna will do this test with more seroconversion antibodies, but eight is enough to know that it definitely works, at least in the test tube.
A parallel trial has been to do the same thing with mice but taking it one step further and this time infecting those mice with COVID-19. The vaccine worked and the mice were protected from the virus.
The next step will be to repeat the process in some hundreds of humans, and then thousands of humans, each with their own individuality, testing for effective production of antibodies and looking for side effects in various sub-populations.
Purposefully infecting the humans, as was done with the mice, is a big ethical issue for any vaccine-development program. Accordingly, the alternative is to test the drug on thousands of people in countries where the disease is rampant. The reason that thousands will be needed is that this type of trial can give false results because of chance involved as to who gets exposed to the disease and who is not.
Much time could be saved if volunteers agree to be infected and if authorities allow for this to be done. Then it would only require about 20 people, purposefully infected, to see if the vaccine protects the volunteers. There would be no placebo treatment of infecting people without the vaccine, so it would not be so-called ‘gold standard’, but it would still provide a very high level of proof. With this approach, the trial could be conducted anywhere, but under strict medical supervision and quarantine, regardless of the community level of transmission.
Moderna is hopeful of having a vaccine ready for licensing by September and then rolling out production from there from late 2020 and through 2021. However, I cannot see this community roll-out starting in 2020 unless they can get ethics approval for purposeful infection.
The history of vaccine trials is very much a story of ‘what can go wrong will go wrong’. The famous Murphy of Murphy’s Law would have nodded his head sagely. So, the journey is far from over. But it is now apparent that vaccines can be manufactured that will lead to appropriate antibody production.
What the scientists now have to be sure about is that the vaccine does not also do unwanted things such as stimulating auto-immunity in some people, such that the body also attacks its own healthy cells. Also, there are big questions about how long the immunity can be maintained. These same issues will be relevant to all the competing vaccine development programs.
Another good thing with mRNA vaccines is that they will be much easier to scale up than all other types of vaccine. For example, quality assurance issues are much easier when working with mRNA than with a vaccine that relies on an attenuated virus. Yet another advantage with mRNA vaccines is that it is easier to tweak the vaccine if the virus mutates.
Even further good news is that if the COVID-19 vaccine works, then similar vaccines can be developed for many other diseases, including some genetic diseases. So, watch out for further news on mRNA vaccines relating to multiple diseases.
A cautionary note, and it is a strong cautionary note, is that all of the above is just one scenario, albeit one that is starting to look more likely. If it were a horse race, then Moderna should now be the favourite, but of course not all favourites make it down the home straight as winners. Horses from other stables will still be favoured by their owners.
The bad news is that if the Moderna vaccine fails it will be because it ‘fell over’. It won’t simply be a case of other vaccines roaring past at speed to the finish line. If obstacles appear for the Moderna vaccine in relation to either non persistence of immunity or emergence of auto-immunity, then these obstacles are likely to affect all vaccines.
There is confusion about asymptomatic cases and population immunity
One of the most contested issues associated with COVID-19 must surely be the extent of asymptomatic cases. Much of the information supplied to the public has been a total muddle.
The initial muddle was created by confusion between pre-symptomatic cases versus truly asymptomatic cases where the disease went through its whole cycle of infection and recovery without any symptoms. The situation then became even more muddled with testing criteria and protocols differing from country to country, and with testing details not explicit.
One of the key issues with antibody testing relates to what is called the ‘specificity’ of the test. This specificity determines the likelihood of false positives and it is different for each test and manufacturer.
Particularly in the early stage of a pandemic, when the number of genuine positives in a population is low, then the proportion of false positives is always likely to be high. People who did not understand these issues have extrapolated apparent but false levels of disease positivity to subsequent stages of a pandemic and this has been a false path of logic.
Here in New Zealand, we can be confident that the number of asymptomatic people capable of transmitting the disease has been low. Otherwise, we would have seen ongoing evidence for community transmission.
When looking overseas, New York City is particularly insightful. This is because the penetration of the disease there is greater than any other city that has detailed data. As of 1 May, New York City had 18,282 confirmed and probable deaths from 166,000 cases. However, a New York State Government study estimated that at that date 20 percent of the population in the city were antibody positive, which would suggest 1.7 million people had been infected. However, not all of these additional people would have been asymptomatic, with many having symptoms but not recorded by the overwhelmed health authorities. Also, some may also have been false positives.
Putting aside for a moment the issue of asymptomatic cases versus symptomatic but unrecorded cases, Worldometers has used the 20 percent antibody-positivity data, together with estimates for both recorded and unrecorded deaths, to then estimate an infection fatality rate of 1.4% at that time, but recognising that this case fatality rate would increase thereafter because of the delay in deaths.
Any further interpretations about New York City depend on further assumptions, in particular what happens to the transmission rate, R, when social interaction restrictions are removed. However, what is clear is that under any realistic version of R as being somewhere between a low of 2.5 and a high of 6 in the absence of social restrictions, then New York City is still a long way from the point where population immunity effects can start to kick in. At that stage, the disease would start to die away. Accordingly, as New York City tries to come back to normal life, there will at some stage be a new wave of illness and death, which can only be halted by a further lockdown.
Shifting to California, where the social demography is different and the lockdown has also been less extreme, the rate of new cases has continued to rise, albeit much more slowly than occurred in New York. The story is similar for Florida. As these states now relax their lockdown policies, it seems logical that case rates are going to rise much more.
In Sweden, the policy has been very much one of flattening the curve but also trying to keep the economy going. The policy of long-term flattening the curve is so they can manage the case load until population immunity is eventually reached. A month ago, they were saying that that they thought within Stockholm, which has much higher levels of COVID-19 than elsewhere in Sweden, they would be seeing signs of population immunity by now.
In contrast, the reality of Sweden now towards the end of May is of no clear evidence of declining cases, despite restrictions broadly similar to New Zealand’s LEVEL 2. Also, on a per-capita basis, Sweden has in recent weeks had death rates higher than everywhere else in Northern Europe apart from perhaps Britain, with Britain being a great mess.
The latest advice (20 May) from Sweden’s State Epidemiologist Anders Tegnell is that he believes about 20 percent of the Stockholm population is likely to have been infected but that antibody levels are much lower elsewhere in the country.
Overall cumulative per-capita death rates in Sweden are now eighth highest across the World, some seven times higher than in neighbouring Finland and nine times more than neighbouring Norway. It is also insightful that the level of economic disruption in Sweden and the extent of recession is broadly similar to the European countries that are in lockdown. At best, it seems that Sweden must remain for a long time at the equivalent of New Zealand’s LEVEL 2.
Searching across the globe, the overarching conclusion in regard to population immunity is that so far there is no evidence of any country coming close to that position. On a global basis, it will be a long journey.
This means that, in the absence of a vaccine, combined with the reality that the world cannot remain in lockdown indefinitely, we have to date only seen the prelude, with the fugue still to come. For those unfamiliar with a musical fugue, it is where the prelude is repeated with variations and amplitude. It won’t be nice.
Even with a vaccine, it almost certainly won’t come soon enough to prevent the global fugue.
I now turn to other areas where there is increasing clarity.
New Zealand can eliminate COVID-19 with tight quarantine and a closed border
The evidence is now compelling that community transmission within New Zealand has been eliminated, at least for the meantime. The provisos relate to there being no virus leakage from the existing active cases together with maintenance of a tight border. Once again, those provisos are considerable.
It would be a tragedy if, having sailed so close to the wind back in March, but having then come though the tempest, we were now to drop our guard. Opening of the Australian border too soon, or an outbreak from airline staff not having to self-isolate, could be our undoing.
Once New Zealand opens the Australian border, New Zealand is no longer relying on its own management, but also that of Australia. Even if Australia is operating at the same level as New Zealand, by creating mobility with a population five times that of New Zealand, the risk also increases in a similar ratio.
Imagine somewhere round twenty planes per day from Australia, disgorging around 3000 people per day and close to 100,000 people per month. Twenty planes may sound a lot, but pre-COVID there were more than that number coming from Australia each day.
It only takes one of those Aussie tourists to be carrying the virus and then become infectious, and then to visit some night clubs, and the virus has spread to the four winds. At that point, New Zealand would have to go back to LEVEL 4. Why would New Zealand risk this without being absolutely sure about sustained zero rate of community transmission in Australia and not just low levels?
Europe and the USA will have ongoing waves of COVID-19 in 2020 and likely beyond
Right now, new cases are declining in most Western countries because of lockdowns. But it is only because of lockdowns. Almost all of these countries are now removing the lockdown screws despite not having stamped out the disease.
Close inspection of the data shows that in many countries the curve is already showing early signs of turning upwards again. Give things another month or two and the embers will be flaming away. What do these countries do then? In comparison, New Zealand is oh so lucky.
The debate between epidemiologists about outcomes in these countries is really only about how quickly the flames will be fanned. Singapore, Mexico and other tropical countries are showing that this virus can thrive in hot conditions and it will not be stopped by summer. My expectation is that in the Western countries the build-up might be slow and intermittent for a short period, but by October, and most likely well before, the virus fires will be raging.
COVID-19 is now unstoppable in many middle-income and most low-income countries.
Despite Western countries reducing their COVID-19 cases under lockdown conditions, the overall trend of global new cases has been upwards for several weeks. It is currently averaging around 100,000 new cases per day. This is because the explosion of cases in middle-income and developing countries is outrunning the short-term decline in the more developed Western countries.
Brazil is the classic example of a country that ignored the risk when it had a chance. Now, it may well be that Brazil will provide the best evidence as to what happens when the curve is not flattened. Despite many Brazilian states trying to flatten the curve, the overall effect has been thwarted by President Bolsonaro having his own unique positions on COVID-19 management. It looks a big mess.
As for countries like India, Bangladesh and Pakistan, if Singapore could not control it in its migrant population – and clearly Singapore has failed in that regard – then what hope do these other countries have with their crowded conditions? They may be able to slow things down, but whether they can flatten the curve, rather than just delay the peak, is another matter.
And what about China in all of this?
In assessing the COVID-19 situation in China, it is essential to separate out health outcomes from politics. It is remarkable that China has gone so close to stamping out the disease. China continues to stamp hard on the embers, with the main focus on returnee citizens from elsewhere in the world. The key province of concern is Heilongjiang with its leaky Russian border. However, on a per-capita basis, China’s active COVID-19 levels, even in Heilongjiang are still very low. There can be no doubt that China understands the importance of continuing to stamp hard and that is exactly what they are doing.
Increasing pollution levels in recent weeks across much of China provide the evidence, with no need for any corroborating statistics from the Chinese themselves, that China is largely back to work. It is not totally back to normal, but there can be no doubt that China is in a totally different situation than Europe and the Americas, and also much of Asia.
There is a real irony that New Zealand (23 active cases), Australia (481 active cases), China (83 cases) and Taiwan (20 cases), together perhaps with Vietnam (58 cases), are the cluster of countries that may be close to eliminating the disease within their borders. Japan (2317 active cases) and South Korea (713 active cases) are the two other large countries that still have some hope, albeit distant, of COVID-19 elimination, but at this stage they are many months behind. Nearly everyone else is at best trying to flatten the curve with no hope of stamping it out without a high-powered and yet to be delivered vaccine.
It is notable that newly elected National Party leader Todd Muller has already flown a kite about re-establishing future travel relations with China. In doing so, he is building a pragmatic argument based on empirical evidence. Not everyone is going to like where that argument leads.
The big picture
It will be a long time, almost certainly at least 18 months, before New Zealand can open its borders beyond a small cluster of Australia, maybe nearby Pacific Islands, and perhaps a set of East Asian countries. New Zealand now needs to work out what its medium-term positioning might look like with much of the rest of the world in ongoing social and economic disarray.
New Zealand is in the fortunate position of having options at this time that few other countries have.
*Keith Woodford was Professor of Farm Management and Agribusiness at Lincoln University for 15 years through to 2015, and retains an honorary position as Professor of Agrifood Systems. He is now Principal Consultant at AgriFood Systems Ltd. One of his interests is the epidemiology of both animal and human diseases. He can be contacted at firstname.lastname@example.org. Keith’s previous COVID-19 articles are available here.