Covid 19

SARS-CoV-2: An Alternative Development Strategy for Second Generation Vaccines aimed at Combatting Escape Variants

Viral 'variants of concern' (VOCs) are a key factor in the development of Coronavirus epidemics. Identifying and tracking them is one of the principal concerns of governments in the developed world, and continues to be a key element in managing the current Covid19 pandemic. Although the initial phase of the pandemic is now waning as more and more people acquire immunity, the virus is likely to become endemic, and the after-effects of its onslaught will be with us for some years to come.

Why are new variants important ?

Although the admirable efforts of our vaccine developers over the past year have paid off remarkably well in providing us with safe and effective vaccines in an incredibly short time, SARS-CoV-2 is here to stay, and we have to find ways to learn to live with it. It is likely that, in common with most successful respiratory viruses, this one will slowly adapt to humans as a new host, thereby reducing its ability to cause us harm over time. However this by no means guaranteed, and if it does occur, it could take years or even decades to achieve.

In the meantime, the only way we can coexist with SARS-CoV-2 variants effectively, without paralysing society by repeated lockdowns, is by establishing and maintaining immunity to the virus in a high proportion of our population. The importance of this has been demonstrated recently in China, where the 'zero Covid' strategy adopted by the PRC government throughout the pandemic, and its reluctance to adopt western vaccine development methods, have left the Chinese population highly susceptible to Omicron BA.n variants. Perhaps not surprisingly, given its record in the West, Omicron is spreading throughout mainland China like wildfire, despite the draconian lockdown rules imposed by the authorities there. See my blog on this subject for more details. 

We know now that the most severe consequences of SARS-CoV-2 infection (i.e. severe lung damage, multiple organ failure and death), as well as the so-called ‘long Covid’ syndrome, usually arise from hyper-immune responses in people who haven’t been exposed to SARS-CoV-2, and therefore have no specific immunity to the virus when it attacks. Those with weakened immune systems are particularly at risk of this syndrome, where the innate immune response to new viral pathogens, which all of us produce in response to a viral challenge, proves insufficient to prevent viral load reaching danger levels following infection.

So far, we in the West have been able to guard against this syndrome almost completely with our current vaccines, and to a lesser extent via the immunity that results from a previous Covid19 infection. Mass vaccination has proved to be the only realistic way of keeping hospitalisations and deaths to a minimum. Letting the virus ‘rip’ to achieve herd immunity was considered as a strategy for UK early in the pandemic, but was never really an option due to the unacceptably high death rate it would have involved. The success we achieved early in the pandemic at keeping the pandemic under control was through social distancing & isolation measures. After vaccines became available the efforts transferred gradually to immunisation and other more intrusive measures were abandoned.

If we already have effective means of protection against serious disease in the form of approved vaccines, why are so-called 'escape' variants such a perceived threat ?

This particular coronavirus has already shown itself to be adept at altering its characteristics. It does this by changing its genetic code for structural components of the virus, notably the spike protein. This is something which occurs naturally due to mistakes in the process by which the viral RNA is replicated during an infection. These changes usually give the 'new' virus no selective advantage over the existing variant, so it just dies out. Occasionally the modifications do give the virus sufficient advantage to start replacing the existing variant in the population, and a new variant is born. 

How quickly the new variant spreads depends on population dynamics, but, thanks largely to air travel, it can be frighteningly rapid as in the case of the Delta variant, which until recently accounted for the majority of infections in Europe and the USA. Omicron has since followed the same pattern and taken over almost completely from Delta worldwide. 

Unfortunately, none of our approved vaccines has proved capable of preventing infection completely although they do help reduce our susceptibility to attack. In the UK, case numbers have remained high since mid-2021 and underwent a significant increase due to the rapid spread of Omicron in the UK. So far, although Omicron has also had a significant effect on hospital admissions, with ca 20,000 covid-related UK cases at its peak, thankfully the number of deaths did not increased to the same extent. 

One rather alarming statistic that emerged early in 2021 was that 40% of all new hospital admissions were double-or triple-vaccinated, which confirmed that even ‘full’ vaccination doesn’t necessarily confer protection against serious symptoms. An additional warning note was that 20% of unvaccinated 18-34 year-olds testing positive for the virus go on to develop more serious symptoms, which can lead to hospitalisation and longer term effects. This is a clear indication that Covid19 isn't just a 'disease of the old' and can produce serious effects in all age groups, even in children. It might arguably be better labelled as a 'disease of the immune-compromised'. None of us should become in any way complacent about SARS-CoV-2's continuing potency or its ability to throw up new challenges.

So far the changes exhibited by the many new variants that have emerged have been 'targeted' at increasing the virus’s ability to infect us; this is likely to be a response to the selection pressure from the various social isolation and distancing measures we have practiced since the start of the pandemic in early 2020. A useful side-effect of these measures has been a marked reduction in the incidence of other seasonal respiratory illnesses, notably influenza.

Over the last 3 years, however, there has been a significant change – in the developed world at least, mass vaccination has immunised well over half the adult population in many states including the UK (ca 85% as of December 2021). Although this was a huge achievement and took place over a very short time period, it has generated a problem of its own. To explain the significance of this we need to look at the recent history of Covid vaccine development.

All our current approved vaccines were developed using the genetic sequence of one of the original 2020 variants of the virus, and all of them were directed against the complete viral ‘spike’ protein without any other viral components being included. 

This was a reasonable response by vaccine developers in early 2020, given the known immunological prominence of the spike protein in other coronaviruses, and their desire to ‘hedge their bets’ on any structural modifications. Many of the variants that have arisen since then have shown multiple changes in the spike protein’s structure and these have the potential to interfere with our antibodies’ ability to bind and neutralise the viral spike. This binding process prevents the virus from 'latching on' to the ACE2 cell receptor and injecting its RNA into the cell, which is a key step in starting an infection. Antibody binding also 'flags' the bound virus particles for destruction by our immune cells.

Some early variants (notably Beta (S.Africa1) and Gamma (Brazil), and more recently Omicron (S.Africa2) all showed signs of escaping at least partially from our vaccine-induced immunity. The Astrazeneca vaccine's efficacy against the Beta variant was actually found to be low enough for its use in South Africa to be abandoned after Beta became prevalent there. It is likely that the selection pressure we are currently imposing on the virus will continue to throw up new variants which are even more effective at evading our antibodies and T Cells. Since we have effectively 'put all our eggs in one basket' by using an isolated single antigen as a target, a new variant whose spike protein 'looked' sufficiently different to our antibodies and T Cells to prevent them recognising and binding to it could in theory defeat all our vaccines at a stroke....

The significant wave of omicron-induced infections still ongoing in the northern hemisphere will continue to promote new variants, and the vast reservoir of as yet unvaccinated people throughout the developing world will ensure the virus continues to circulate. China is an obvious example of what can happen in a largely unvaccinated population - there will be more to come. Our very success in vaccinating ourselves in UK means that  we may be one of the first nations to fall prey to escape mutations.  Another problem is the time taken for our immunity to decline following double-and triple-vaccination. Based on data obtained so far, acquired immunity is unlikely to be effective for more than ca 6 months in most 'healthy' individuals and is likely to  decline much faster in the elderly and the immuno-compromised. Booster jabs were actively implemented in UK in 2021 for most age groups, based on this assumption, and there was much emphasis during that autumn on the importance of boosting immunity against both SARS-CoV-2 and the current flu virus strains before the winter 'flu' season.  Over 75s were offered a second booster  in Spring 2022 and again in Spring 2023 and 2024, while an autumn booster was offered to over 50s in Autumn 2022 and 2023. Re-boosting for younger age groups will be even more important for Autumn 2024, given many will not have been immunised for over a year and Omicron has once again surprised us with a new variant and another concomitant wave. There is also likely to be a resurgence of flu through 'novel' strains after three reduced flu 'seasons' between 2021 - 2023.

UK vaccination efforts have redoubled since Omicron came to light, in attempt to maximise protection against new variants and minimise hospital admissions. First generation 'tweaked' vaccines, based on current and recent VOC spike protein structures, are also being investigated with a view to their use as 'enhanced' boosters if they achieve approval next year. The Moderna Spikevax bivalent whole S-protein vaccine was the first to be appproved closely followed by the Pfizer bivalent product, and both are used during national vaccination campaigns. 

On the research front, few candidates which depart from the S-protein only  'party line'n have made it into clinical development. An oral vaccine using an mRNA vector coding for all 3 surface exposed proteins (S, E and M) and using Virus Like Particle (VLP) technology, has been approved for Phase 1 trials in a number of territories. Two other multivalent vaccine candidates are in pre-clinical development and IND/CTA applications for human dosing were planned for late 2022  (see link to AZD2816 ongoing study, and download the full paper from the downloads page for more details). The adenoviral vector approach has now largely died out, with the mRNA vaccines now taking the lion's share of marketed vaccines. The first truly RBD-directed candidate likely to be approved, Moderna's Spikevax upgrade mRNA-1283-P301, is now undergoing Phase 3 trials.

How likely is it that more effective escape variants will evolve - and then actually become sufficiently predominant to cause problems? 

This will depend primarily on two things - the extent of selection pressure and the 'room for manouevre' the virus still has available to effect changes in its structure without compromising its ability to infect...and replicate. At present it looks highly likely that such variants will continue to emerge and take hold - the new Omicron variant has now become dominant and has now replaced Delta entirely worldwide. Omicron also looks to be more capable of evading our pre-existing immunity, although the extent of this is still not fully characterised. Early data from SA population studies suggested it might be less likely to cause serious illness and death - data that has since emerged from early UK studies and population statistics do seem to confirm this,  which is good news indeed. 

However, the pressure on our hard-pressed NHS is still inexorable (largely due to poor coordination with the adult care sector and significant staff shortages across the board) and is expected to continue throughout the summer. Any improvement as a result of the newly elected Labour regime will be protracted, given the existing 7.5 million long waiting list, and the likelihood that the can will once again be kicked down the road on a much needed and radical funding model re-vamp. 

The NHS was designed in the 1940s for a completely different different set of demographics, and no one could reasonably expect it to be capable of satisfying the demand that is now being placed on it. Many of those who are experiencing difficulty obtaining consultations and treatment believe it is already unfit for purpose, and may be literally on the verge of collapse due to the combined effects of a rapidly ageing population and the after-effects of Covid. There is no obvious solution to this problem while the system remains entirely state-funded through taxation.

At present it's not possible to determine whether the apparent reduction in the severity of Omicron infections is due to its inherent properties, or to our increased levels of immunity as a result of boosting / increased disease incidence. The failure of % age ICU occupancy and death rates to increase in parallel with viral transmission, and the fact that almost all severe cases are unvaccinated, suggests pre-existing immunity is likely to be the primary cause. If so, continued and effective immunisation top-ups going forward will be essential in controlling the disease. The advent of two new and evidently more immune-evading Omicron variants in Australia in early 2024 (FLiRT and FLuQE) and their subsequent rapid spread to the Northern hemisphere suggests that the virus is still very much 'in control' and may now be adapting to widespread vaccination by immune-evasion tactics rather than simply upping its infectivity as we saw in early variants. Interestingly, the virus appeared to have traded some of its infectivity for increased immune evasion in FLiRT which it has now regained with the advent of FLuQE.

There are a number of possible scenarios for the eventual fate of this virus, however - download the main article from the downloads page for a more detailed discussion on the likely progress of the pandemic and any future epidemics. 

The main concern of virologists and epidemiologists is that the virus may jump the species barrier back into one or more animal hosts with which humans have close contact, then re-emerge into the human population in a more comprehensively mutated form against which we have little or no immunity. This is a distinct possibility, given the  continued propensity of some nations for handling and trading in exotic animal species, and the high worldwide prevalence of the virus. Coronavirus 'species jumps' have already happened twice (SARS-CoV-1 and MERS-CoV were both of zoonotic origin). Conspiracy theories notwithstanding, a similar zoonotic route in Wuhan, China is most likely to have been the original source of SARS-CoV-2. The difference this time round is that the virus is so widespread in the human population - this makes inter-species transmission much more likely, and more difficult to guard against. All the more reason for a more robust and comprehensive approach to vaccine design that allows for rapid adaptation to new variants....

On a practical level, how can we best keep track viral evolution and spread ? Lateral flow tests were widely available after early 2021, and provided a rapid and relatively cheap way of identifying those cases that were most likely to be infectious. These tests were free until early April 2022 but are now chargeable and have sadly largely disappeared from our domestic 'armory'. When it came to 'official' testing for the virus, gold standard PCR tests were the only acceptable option. It is no coincidence that negative PCR tests  were required as evidence of non-infective status for entry into many countries including UK, even for double-vaccinated travellers, until travel restrictions were finally relaxed in early 2022. This was because PCR is the only method we have which can be used to identify and track new variants, and the swabs and processing required for lateral flow weren't compatible with follow-up PCR testing. There was much concern in UK government circles 'pre-omicron' that a new variant could slip through the net undetected if the much cheaper lateral flow tests were allowed to replace PCR as the initial screening test on cost grounds, especially for those travelling from so-called 'red' (and former 'amber') list destinations. However, the travel industry fought hard to get lateral flow adopted for fully-vaccinated travellers on convenience and cost grounds and this was approved in autumn 2021. Requirements for testing were dropped in 2022.

Perhaps predictably, UK rule changes and the general relaxation of worldwide travel restrictions actually did result in very rapid worldwide spread of the Omicron variant following its first identification in South Africa. Despite the ensuing re-tightening of travel restrictions, the 'genie' proved unstoppable once it got 'out of the bottle' and Omicron rapidly  spread worldwide. We should learn the lesson from this when assessing how to spot, and then deal with, the next VOC. Unfortunately, now that we have 'let down our guard' by abolishing free testing, and lifting all legal restrictions our ability to do this will of necessity be compromised.

We can only hope that the continued vaccination effort combined with immunity from previous exposure will prevent a general Covid resurgence as a result of the general relaxation of control measures....

The latest variants in the Omicron series to hit the news (FLiRT and FLuE) appear already to be spreading even faster than the previous B.An sub-variants did. So far most cases have displayed relatively mild symptoms. This may indicate the virus is following the normal gradual progression towards a milder symptom profile. We should however be cautious about jumping to this conclusion. In practice, much of the reduction in serious disease is likely to be as a result of the vaccination effort combined with infection-induced immunity. These particular variants do also seem to be more immune-evasive, which sounds an additional note of caution regarding the virus' future adaptive direction and its ability to overcome our immune defences. 

However, provided we are able to maintain immunity, reguler immune top-ups may still enable us to maintain  'normal' life and avoid future social distancing and (heaven forbid!) futher lockdowns. If so, it will be good news indeed - time will tell.

I believe we should still broaden our approach to vaccine development in the light of the continued arrival of new ‘variants of concern’, and the virtual certainty that more will arise in the near future. 

Immunity is still key to our successful coexistence with this virus - 'zero-Covid' strategies such as that doggedly applied in China at the whim of its leader for so long simply do not work. 

The single-antigen vaccine approach using whole S-protein is clearly being rapidly and consistently out-manouevred by the virus. A multi-antigen approach including viral components which are less subject to mutation is called for with 2nd generation vaccines. This will allow us to achieve and maintain 'steady state' effective immunity and live effectively with the virus as a developing endemic. 

A particular worry, though, as already discussed, is further zoonotic viral transformation in intermediate animal species, followed by migration back into the human population, which could occur at any time. Farmed animal species such as mink have already caused scares with mutated forms of SARS-CoV-2, and there will be more to come. Vaccines using highly conserved antigens may be our only hope of pre-empting further Coronavirus pandemics occurring as a result of viral zoonotic 'escapes'.

 Although this is an important area of vaccine R&D, and could turn out to be a 'game changer' for the reasons already discussed, it has one important caveat.  Any progress we could make in this area de novo would probably not be in time to overcome any escapes from existing or upgraded 1st generation vaccines that might occur this autumn and winter. This is because of the established lead-in development and approval times required for any new vaccine, even if fast-tracked. 

If successful, though, such a 2nd generation vaccine product could potentially provide a backup from mid-2025 onwards in case our existing vaccines and their 1st generation 'tweaked' bivalent successors, start to fail. Given the vast amounts of resource which has already been poured into combating this virus, it would seem indefensible to 'spoil the ship for a ha'p'orth of tar' as the old saying goes, by ruling out this opportunity on cost grounds. For obvious reasons, time is of the essence in coming to a decision on commissioning any new projects....

I recently authored an opinion paper entitled ‘SARS-CoV-2: An Alternative Development Strategy for Second Generation Vaccines Aimed at Combatting Escape Variants’ as a contribution to the vaccine development effort. The paper recommends a strategy involving new viral antigens, and discusses the practicalities and limitations of this in detail. It also raises the issue of whether any structural changes exhibited by new escape variants will compromise our ability to detect them, and the antibodies we produce against them, using our current tests. Some final thoughts on the likely future course of the pandemic are also included, together with recent updates to vaccine development progress.

The content of this paper has already received a favourable review from one expert in the field. Some very recent evidence has also confirmed that pre-existing immunity to SARS-CoV-2 and other types of Coronavirus in the general population is mediated by highly conserved 'non-spike' proteins, giving additional weight to the argument for including these as novel targets in our 2nd generation vaccines. 

Given the current situation with Covid 19, and the development of escape variants as a ‘hot topic’, I’d like to offer an updated version of this paper online for review and comment. 

I intend to continue updating this page and the full paper regularly in the light of any relevant developments. Please see footer for current version date. 

You can view and/or download the full paper by following the instructions on the downloads page on this site. 

I would welcome any comments or suggestions you may have– you can contact me using the form on the Contacts page of this website.

Update 7.7.23: Although the pandemic has now been downgraded by WHO, Covid is still with us..and is here to stay.

Covid19 has been a salutory experience for us as a species. SARS-CoV-2 is still very much in evidence and has developed a formidable capability to infect us despite our continued fight against it. Make no mistake, it can still kill, and those who are unfortunate enough to be unable or unwilling to accept the vaccines or who have compromised immune systems, are still at high risk. 

Hopefully our experience since those fateful weeks in the run up to our first lockdown will have convinced us that we need to be mindful that pandemics are likely to be a regular occurrence in the 21st century, and that the next one stands a good chance of being caused by another Coronavirus of zoonotic origin.

Perhaps the greatest risk in the medium term is from a new variant of SARS-CoV-2 which migrates into one or more animal vectors and then re-emerges in humans in modified form. This is likely to be sufficiently different antigenically to defeat our existing acquired antibody and T-cell populations.

Any close contact between humans and such animal vectors is likely to hasten this process, so should be avoided wherever possible.

The ongoing risk justifies the need for enduring Coronavirus vaccine ‘cover’, preferably using mRNA platforms involving viral elements which are likely to be common to many strains and of low mutability. The vaccine development effort needs to be maintained and properly resourced - a big ask at a time of enforced austerity, no doubt, but vital to our health interests...

Direct Link to publication: https://drive.google.com/uc?export=download&id=1Tz451xiTm_bpFL3bSqq-JoO_GUQ78sHC

First published 18.6.2022; Revised 12.7.2024