It appears that the vaccine rollout will not significantly shield us from a winter wave, writes Neil Stacey.
South Africa’s second wave of Covid-19 infections is rapidly abating, with daily infections in apparent freefall.
The 7-day rolling average of daily infections peaked at 19 042 on the 11 January, and has dropped sharply to 8141 as of the 28 January. It will continue to drop, though it is unclear exactly how far.
After our first wave of infections, the daily rate of infections settled at a steady rate of around 1500 cases per day, and we may see something similar occur over the next few months, though the only method available for estimating the exact level is guesswork.
At the change of season, however, we are likely to see the onset of a winter wave of Covid-19 infections.
The virus is known to be more transmissible in cold weather; Europe and North America both experienced their largest surges of infections starting at around the onset of autumn. The experience of the United States is particularly instructive - they had a second wave driven by behavioural shifts, followed by a more severe third wave driven by colder weather.
There is a distinct likelihood that, without effective measures to mitigate it, South Africa could experience a winter wave more severe than the one we are currently emerging from.
Far larger second wave than expected
Our second wave was far larger than most scientists expected, driven not just by shifting behaviour and high volumes of travel during the festive period, but also by the emergence of a new Covid-19 variant (B1.351) which appears to exhibit higher transmissibility, arising from the N501Y mutation which is present also in the B1.1.7 variant observed widely in the UK.
Both of these variants rapidly supplanted the previous variants (hereafter referred to as ‘vanilla Covid’) and became prevalent in the respective populations where they were observed.
The prevalent variant in South Africa, B1.351, also carries the E484K mutation, which appears to give the virus some degree of resilience against the immune responses to vanilla Covid. In-vitro (test-tube) assays exposed cultures of B1.351 to serum samples from patients who recovered from vanilla Covid, and it was found that some of the serum samples showed little or no neutralising antibody activity, and many showed reduced activity, suggesting that the immune response to vanilla Covid is not entirely well-suited to neutralising the new variant.
These in-vitro tests never tell the full story, and neutralising antibodies are just one (albeit significant) part of a real-world immune response, so it is impossible to infer quantitatively how in-vitro differences will translate to real-world immune escape.
In additional to considerable variance in individual immune responses, there are also fundamental differences between the immune responses to vaccination and natural infection, as well as between the immune responses to specific vaccines, so genuine real-world data is needed to make any statements about the efficacy of vaccines and prior infection with vanilla Covid against the new variant.
What course will Covid take?
With the new variant comprising the majority of cases in South Africa, knowing how much immune escape we can expect is critical if we are to get a sense of the course that Covid-19 is going to take for the foreseeable future.
In the short-term, the performance of Astrazeneca’s vaccine is particularly important; our Phase 1 inoculation program consists solely of 1.5 million doses of the Astrazeneca vaccine, which will be used to vaccinate 750 000 healthcare workers in a two-dose protocol.
At this stage it appears vanishingly unlikely that any other vaccines will be procured in time to mitigate the winter wave, should it arise.
The Astrazeneca vaccine showed overall efficacy of 62% in its Phase 3 trials, but it is not clear what degree of immune escape can be expected from the new variant.
Fortuitously, sheer luck has just delivered us some instructive data from which we will be able to infer some reasonable estimates.
The Phase 3 trials of the Novavax and Johnson and Johnson vaccines just happened to run an arm in South Africa, after the new variant had become prevalent*.
Looking specifically at the data from those South African arms will give an indication of the efficacy of these vaccines against the new variant.
Comparing those efficacy figures to those observed in the arms taking place elsewhere will also give an indication of the degree of immune escape specific to the new variant, and may enable us to make broad estimates of the efficacy of vaccines that were not tested here.
Novavax released the results of their trials on the 28 January, and Johnson and Johnson released theirs on the 29 January.
The Johnson and Johnson vaccine uses an adenovirus vector to deliver the Covid-19 spike protein, the same basic mechanism as the Astrazeneca vaccine, but is distinct in that it uses a different viral vector and is a single-dose protocol as opposed to AstraZeneca’s two-dose protocol. Nevertheless, the efficacy drop-off for that vaccine in South Africa as compared to elsewhere will give us some indication of how effective the AstraZeneca vaccine will wind up being.
Johnson and Johnson report an overall efficacy of 66%, with 57% in the South African arm.
This is positive news for South Africa in the long term.
We have committed to purchasing 9 million doses of this vaccine, sufficient to inoculate a large portion of the population, and the single-dose protocol coupled with comparatively simple storage requirements mean that its distribution will be relatively straightforward.
Efficacy of 57% might not sound spectacular, but vaccinated individuals who catch Covid-19 anyway will still have some immune advantage over unvaccinated individuals, and so the rate of severe illness is diminished, as is onward transmission of the virus, because of lower viral load. In short, the actual reduction in disease burden exceeds the published efficacy.
This data is also positive for us in the short term.
It suggests that we can be fairly confident that the Astrazeneca vaccine will retain efficacy in the region of 50% against the new variant, and can therefore be expected to quite considerably reduce disease burden among our healthcare workers as they deal with winter wave.
The Novavax data is less directly applicable to the South African situation, but nevertheless give us a fair amount to examine. Their media release makes the following main claims:
- The efficacy in the UK trial was 89.3%. This is based on 62 cases of symptomatic, PCR-confirmed infection. 56 of those infections were in the placebo group, 6 were in the vaccinated group. Of those 62 infections, 32 were found by gene sequencing to be the B1.1.7 variant, 24 were vanilla Covid, and the remaining 6 were not sequenced.
- The overall efficacy in the South African trial was 49.4%, based on 44 Covid-19 infection events, 29 in the placebo group and 15 in the vaccine group. 27 of those cases were gene-sequenced, and of those 25 were from the B1.351 variant.
- Approximately one third of the participants in the South African trial tested positive for existing antibodies in serology studies, and no significant difference was observed in infection rates between those who tested positive for pre-existing antibodies than those who did not. In a webinar, Prof Shabhir Madhi, the principal investigator, indicated that the same rate of infection (~2%)** was observed in participants with positive serological findings as in those without, and stated further that this indicates that prior infection with vanilla COVID does not confer significant resistance to the new variant.
The first comment to be made is that the statistical strength of these efficacy trials is such that we can be broadly confident in qualitative conclusions but the quantitative efficacy numbers involve considerably possibility for variance. While the sample size of people recruited into these studies is very high (>15 000 in the UK trial, 4 400 in the SA trial), the actual number of Covid incidents is small, 62 and 44 respectively, amounting to a decidedly small sample size, lowering statistical confidence.
There are some interesting observations that can be made on the South African data.
The 44 Covid-19 cases, from 4400 participants, amount to approximately 1% of participants contracting Covid in the period from September to mid-January. In the same time-frame, approximately 750 000 Covid cases were reported in South Africa, roughly 1.25% of the total population.
Factoring in the 49% efficacy in the experimental group and therefore roughly 25% reduction in infection in the overall trial population, there is a near-exact match between the infection rate in the trial population and in the overall population in the same period, which is a remarkably neat conformity.
This neat correlation vanishes completely in the serology testing for prior infection.
Reported cases in the general population prior to the trial period amounted to ~1% of the total population, but serological testing yielded 30% positive findings.
There is no easy way to reconcile this extremely high rate of positive serological findings with the comparatively low observed spread of the virus prior to the study. The surface explanation that 30% of the trial population had been infected prior to September is difficult to accept at face value.
It has been shown in previous research that these serological studies can yield false positives arising from cross-reactivity with antibodies for other coronaviruses, and that the rate of these false positives varies considerably among different population groups as well as between specific brands of test.
This factor, along with the vast discrepancy between the serology numbers and reported cases, would be sufficient to regard as suspect the claim that prior infection with vanilla Covid does not confer resistance to infection with the new variant. The only statement that can be made with confidence is that positive serological findings do not imply resistance to the new variant, an important observation in its own right.
If the actual prevalence of prior infections were to lie closer to the 1% of reported cases among the general population than to the 30% of positive serological findings, or even somewhere mid-way between the two, then the data simply cannot support any claims about relative risk of infection associated with prior infection.
Even if the serological positives were taken at face value, there are further confounding factors that would distort the correlation. The first of these is that the initial likelihood of infection is affected by differences in behavioural patterns, which implies that the cohort exhibiting prior infection would have, overall, presented a different behavioural risk profile than those not exhibiting prior infection.
Additionally, individuals who have knowingly recovered after having been infected can be reasonably assumed to have modified behaviour.
In summary, the claim that prior infection with vanilla Covid does not confer resistance to the new strain is not well supported by the data presented. Though there is good reason to believe that the new variant does have some ability to evade immunity acquired from infection with vanilla Covid, the most reasonable assumption is still that a prior infection will likely confer some degree of immune advantage.
Nevertheless, the Novavax data does present concerns for the South African vaccination program.
A decline in efficacy from 90% to 50% is a significant degree of immune escape, a trend that suggests that vaccination in general will be less effective in the South African context until vaccines updated for the new variant become available. It is not yet clear what the exact time-line for that will be.
Some of the vaccine developers have indicated that modifications could take as little as three weeks to develop, but it is still presumably necessary to run trials on the new versions before regulatory approval can be obtained. Such trials take time and will likely face the obstruction that they will only be able to ascertain efficacy if they are run in populations where the new variant is already highly prevalent.
Manufacture and distribution of doses also take up time, as does the actual administering of those doses, and the immune response is not immediate. It is difficult to envisage any way that the turnaround time from the start of development to a meaningful immune response on a population level could possibly be less than four months.
For the immediate future, therefore, we can assume that the new variant’s immune escape will have some impact on our vaccination efforts as well as somewhat diminishing the effects of naturally-acquired immunity. With only 750 000 people, or fewer, likely to be inoculated before the winter wave begins, vaccination will not have a significant quantitative effect on population-wide spread, and there is reason to be less than entirely confident in the effectiveness or prevalence of naturally-acquired immunity in our general population. We may not be going into winter completely naked, but we have allowed ourselves to be caught with our pants down.
* Strictly speaking, the Novavax trial in South Africa is a Phase 2b trial. This distinction is not tremendously significant.
**I am not able to entirely reconcile the quoted 2% infection rate with the ~1% rate determined by taking the number of Covid incidents divided by the trial population. The discrepancy may arise from the 2% referring to Covid outcomes over a longer period than the primary endpoint used in determining vaccine efficacy (28 days from inoculation)
- Dr Neil Stacey is a lecturer in Biomedical Engineering and Chemical Reactor Design at Wits University, and since 2020 has been a key member of a multi-institutional, multidisciplinary research collaboration developing cost-effective new treatments for critically ill Covid-19 patients.
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