I mean, who wants to say “living with COVID” amirite? The connotation is that it’s just a necessary thing we have to do. But really, at some point, it kind of is necessary just because most of the world hasn’t made good choices to this point, and the virus is so widespread that it would take a massive collaborative effort using better vaccines to ever eliminate COVID-19. Personally, I don’t think it’s realistic to suggest we’re not, let’s say, “living next door to Alice” (here, Alice is the virus, SARS-CoV-2, not the disease, COVID-19), for at least years to come.

That’s all a bit hopeless, isn’t it?

I don’t think so. Let’s use Australia as a case study because it did so well for so long.

A recent 12-24 period recorded 35,000 positives in Australia. To eliminate the virus from Australia now is almost impossible without:

• return of border controls
• return of lockdowns
• return of masks
• return of density caps
• return of contact tracing (currently out of control) to capture all cases and contacts
• need for PCR – not rapid antigen tests – to catch every positive person and their contacts as early as possible
• return of all quarantine and isolation of cases and contacts

Essentially reinstating every tool, we were previously using to allow us to rid the country of every infected person. After which, we’d have to instigate a surveillance system to test every incoming/returning traveller with a possible case of COVID-19 (a lot harder to pick clinically than measles is for example) for SARS-CoV-2.

Can I remind you that a big chunk of cases are asymptomatic and that the symptoms of COVID-19 can include…

• fever
• cough
• tiredness
• loss of taste or smell
• sore throat
• headache and pains
• diarrhoea
• rash on skin
• discolouration of fingers or toes
• red or irritated eyes
• difficulty breathing or shortness of breath
• loss of speech or mobility,
• confusion
• chest pain

Easy to pick that case up, right? No, it isn’t. It needs a laboratory test. It has all along except in rare cases of severe disease. That would have to be done before contact with others, and it would need to be repeated 3-5 days later if you were serious about catching an incubating infection. We’re simply not planning to do that.

We’d have to hunt down every case with testing levels at or beyond the level we have now, along with a fully compliant population.

Eliminate virus or disease?

Now the knowledgeable among you will be saying that really, we want to make the country disease-free rather than virus-free. Fair enough. We’ve done that with, for example, measles and rubella in Australia.

Vaccines have already gone a very long way toward reducing the levels of severe COVID-19. Not to zero, but then they also don’t do that for other virus-induced diseases.

Biology is a complex beast. There are always people for whom vaccines don’t work or work less effectively. But just as we don’t effectively protect them from death and harm due to influenza, respiratory syncytial virus (RSV) or human metapneumovirus (HMPV) disease, to name a few, we won’t be able to prevent all harm from SARS-CoV-2. Even with better vaccines.

What we can do and have done

We can treat disease better – from steroid treatment to patient placement to new and emerging antivirals and antibody cocktails – we have quickly increased the arsenal of ways to reduce severe disease.

We can slow transmission – although that isn’t happening in a way that meets expectations almost anywhere (I see you, Kiwiland), even with some mask use. We know that high vaccination levels don’t wholly stop SARS-CoV-2 from spreading.

Immunity from vaccination and infection does reduce the severity of disease because that’s biology and immunology. This virus hasn’t turned it on its head, even if the messaging is confusing and seemingly contradictory.

Keeping in mind that severe disease and death were already at the pointy and rare end of SARS-CoV-2 infections – even though that harm has been tremendous because infections were in such vast numbers. But vaccination has further reduced severe outcomes. Wherever this has been looked at. And with the first booster/3rd dose this is even more effective at reducing disease after infection.

Perhaps soon, we may stop to think about what we’re expecting to happen with this virus. Are we expecting things to turn out better than we have ever expected with some other far less well quantified viral and bacterial diseases that kill and cause a range of harms (also nowhere near as closely studied as COVID-19’s effects have been)?

It might be time to utter those horrible words again – how does COVID-19 (Omicron in highly vaccinated parts) compare to flu at the moment. In 2022 Aus saw a flu epidemic and those cases were not as numerous nor serious at scale as the SARS-CoV-2 epidemic that was running in parallel.[U1] It would be nice to have this as a global discussion and not assume this means anyone is downplaying the impact of COVID-19. Perhaps an international health authority could take the lead here; maybe a worldwide simulcast seminar (gasp – think of the educational opportunities)!

But communication is something we aren’t doing well in this latest chapter of the Book of COVID (I think we’ve just written notes on the ‘test wars’ chapter, mainly having completed the ‘vaccine wars’ draft).

Everything is messy right now and the public has not been kept up on what’s happening for a while. We’ve learned nothing about keeping the public informed these past two years, have we?

So what might living next door to Alice look like?

The graphic below got me into trouble on Twitter as it came across as too defeatist for some. The reality is that we haven’t done enough to get rid of the virus, and so long as a virus circulates, there will be asymptomatic, mild and moderate cases of COVID-19.

Australia was in a great place to test what was possible. In the State of Victoria, a Wave that reached over 720 cases per day at the end of July 2021 was turned around and driven to zero. At the beginning of September 2021, when Delta started to appear in Victoria again, the will just wasn’t there for another prolonged battle.[3,4,5] The State of New South Wales had already acquiesced to its wave and, after locking down for many weeks, made a conscious decision to discard a COVIDzero approach and more to suppress spread while getting vaccination-induced immunity levels up. That epidemic triggered seeding events all over Australia and into New Zealand.[6] It was apparent then that we had shifted gears and that we couldn’t control this efficient respiratory virus again and again and again. And if we couldn’t handle it at dozens to hundreds of cases, we should honestly embrace the reality that we won’t get to a place where we can control it at thousands and tens of thousands of daily cases, be they local or worldwide. And at some point soon, testing levels will drop as the public realise there is little point in queueing and getting swabbed or paying for rapid antigen tests (RAT) when there are few conditions in place to do anything with those results. Slowly those who are sick “enough” or need evidence that they are infected will get tested. Fever clinics and drive-through testing will slow down and pack away. We will know only very approximately how many cases are in the community from at that point. This is a significant shift from the super intense scrutiny of case numbers we’ve had in Australia. Then the media will also stop caring as much. Politicians will have stopped minimising the pandemic and moved on to their pre-election agendas. Sniping at experts, academics and scientists willing to help the public understand what politicians want will fire up – oh sorry, that’s already happening.

In the future – things should return to something like how we used to “live with” influenza or RSV or MPV. All viruses to which we begin to gain some immunity from birth. We don’t all get infected at birth – that’s not what I’m saying – but some of us do, and get exposed throughout life thereafter.

Maybe, possibly, perhaps, this future will even be in 2022 after so many of us get infected on top of being fully vaccinated (those of us who were lucky enough to be). That might be a bit soon. Whenever this future happens, SARS-CoV-2 in some forms, versions, variants or varieties will still be there, as will illness and deaths and research reports about all that SARS-CoV-2 is capable of.

Even with better, more protective vaccines, there will be those with waning immunity. There will be new birth cohorts with no immunity. There will be those who don’t get vaccinated. There will be those with immune systems that don’t work as well as needed. There will be some with risk factors that may override the protection afforded by vaccine immunity, subjecting them to a baseline of worse outcomes. Together these people will likely see more severe COVID-19. This is a tale that can also be told about other infectious diseases. There is always a proportion we can’t protect. At least, not unless we keep everyone in a bubble or on an IV vaccine or immune stimulant of some sort. Or we collaborate to make the world a better place (but I have no hope of seeing that reality in my time).

We also know that infection and transmission can still happen in the presence of immunity – whether vaccine or infection-induced. Again, this is biology. SARS-CoV-2 will therefore bounce around for a range of reasons – some of which I hope I’ve covered above. I may add some in response to the feedback I get to this post.

Most of the time, SARS-CoV-2 will be passing from person to person at low levels, constantly evolving, as all the other respiratory viruses do all the time (just because you don’t hear about them or they’re not causing an epidemic, doesn’t mean they’ve disappeared!).

Occasionally when habits change, such as when we huddle inside in what will likely remain poorly ventilated spaces for some years yet, to escape the heat or the cold, or when the size of a suitably non-immune population reaches a tipping point, occasional surges or epidemics will result. There could be a role for more dramatic viral changes as well; this virus has infected many animals in the past two years. But it’s my opinion that SARS-CoV-2 will maintain enough transmission to stick with us for many years yet.

It’s just a graphic, not a model.

The below image was an idea I had to try to visualise what life might be like in one version of a future. To be clear, that future could be years away. I put it out on Twitter, and it got refined a little in response to a range of feedback.

It starts with a largely well-vaccinated population with immunity (left-hand side).

Biology and immunology have shown repeatedly that with great immunity (to an infectious thing) comes great protection from the worst of disease (due to infection by most of those things). But we know with SARS-CoV-2 this is proving to be more complex than that.[16, U1]

In the future, from this mythical future global population (thick central orange line), I’m presuming here that the vast majority of infections will be manageable outside of a hospital. That’s not prophetic – because that’s the case now! But even moreso than they are now.

Some infections will not be, and those people will need more care than can be managed at home. Some will, tragically, die. Disproportionately among the unvaccinated and those most at risk like the elderly. You can see for yourself a pre-Omicron estimate of how age is critical to understanding death (don’t use a single “fatality rate” to describe the impact of SARS-CoV-2).[13]. To be clear, I’m not advocating for any of these deaths, by the way! This is the path that we are all on, though. Like it or argue against it – we’ve done nothing but create and sometimes refine or improve this path.

The graphic also shows the emergence of new variants – when I made it, there was no Omicron. Its appearance proved to be a great example of the puff of purple virions in that bottom loop.

I expect childhood vaccination programs to reduce an already low likelihood of severe disease in the young. Such programs will create an immune population that will travel with that immunity. Don’t forget SARS-CoV (the original). Cases still have cellular immune memory a dozen years later, which probably protects from severe disease (because that’s how it usually works). SARS-CoV-2 vaccines also generate such immunity, even across the variant spectrum.[10]. Immunity will dampen severity, except where immunological imprinting causes specific issues.[16,U1]

Life (right-hand side) will contain additional shots and better vaccines or boosters to prevent disease and new drugs to treat the condition. Ongoing reinfections will happen – as they do for other viruses – but these will mostly be non-severe diseases or be asymptomatic. Mostly does not mean all the time. You could drive a truck through what’s left over from “mostly”.[U1]

Future variants – the bottom loop – are not guaranteed to be milder than previous ones. They just need to have some advantage that allows them to keep passing from one cell sack (host) to another. SARS-CoV-2 being “endemic” doesn’t imply a magical definition of mildness, just of being with us, somewhere in the world, all the time. The only thing that will change this is s vastly improved vaccine along with a global push to eliminate COVID-19.

Whatever mutations accompany a change to a virus that makes that viral variant better in a significant way will stick. If other mutations co-occur that cause us to slowly melt or bleed from the eyes, that’s what will happen. But immunity has reached levels that it’s never been at before, so it will look like new variants aren’t as bad for all but the more nasty, virulent newly emerged immune escape variants. Don’t fall for that “Ohhh, but it wouldn’t be advantageous to the virus…” unimaginative rubbish. If a virus passes on its genes before its host dies, then mission accomplished in virus land. You could still bleed from the eyes & pass on a virus. You could melt into a puddle of protein and lipids much later on & still pass it on to many of that’s just the way the virus variant transmission cookie crumbled.

Immunity developed after a symptomatic infection dramatically reduces the risk of future severe disease from reinfection. That immune memory lingers in most of us for life in some form at some level of effectiveness.

But Living Next Door to Alice is still confounded by one big unknown.

The exhausted elephant in the room

Many people infected by SARS-CoV-2 recover without problems. However, some proportion is left with persistent symptoms commonly known as “long COVID” or “long-haul COVID”.[7,9]

An agreed-upon global definition, post-COVID condition (PCC?), aims to help focus research, clarify terminology for medical use and better define and capture cases of PCC.[9] PCC occurs in those with a history of probable or confirmed SARS-CoV -2 infection, usually three months from illness onset, with symptoms (no minimum number) that last for at least two months and cannot be explained by an alternative diagnosis.[9]

We know that SARS-CoV-2 can travel all over the body and infect a wide range of our cells. But PCC remains unclear but to many very worrisome black box of unknowns.

Some of the questions still outstanding include:

• What proportion of total COVID-19 cases ends up with PCC?
• What proportion of those with PCC had no symptoms or had a mild, moderate or severe disease course following SARS-CoV-2 infection?
• What proportion of those with PCC has a pre-existing or underlying condition?
• Does immunity from vaccination prevent, modify or have any impact at all on the number of people who acquire PCC?
• What is the impact of vaccination on PCC once you have it?
• What else might help treat or manage PCC – from medicines to exercise to vitamins…?
• Is the length of PCC affected by age, sex or comorbidities?
• Are there any factors that affect the prognosis of those with PCC?

Summary

It does seem that the latest and most ubiquitous variant, Omicron, causes less severe disease compared to the Delta variant.[8,12,13,14] Vaccination – especially after boosting – and prior infection also help to modify disease outcomes further to be less severe [8,13]. Still, PCC casts a shadow that remains a lingering concern to be addressed in this pandemic.

Apart from PCC’s many unknowns, we have entered into the chapter that I’m calling “Living Next Door to Alice” for now. I think it could be one of the last few chapters in this book.

Updates

1. [U1]

Reference

1. Disease Elimination
   https://www.burnet.edu.au/programs/27_disease_elimination
2. Infectious and communicable diseases, AIHW
   https://www.aihw.gov.au/reports/australias-health/infectious-and-communicable-diseases
3. Victorian Premier Daniel Andrews unveils roadmap to easing restrictions as he concedes cases may not go down
   https://7news.com.au/lifestyle/health-wellbeing/victorian-premier-daniel-andrews-unveils-roadmap-to-easing-restriction-as-he-concedes-cases-may-not-go-down-c-3840699
4. Victoria abandons COVID zero but national plan in doubt
   https://www.afr.com/policy/health-and-education/victoria-abandons-covid-zero-but-national-plan-in-doubt-20210831-p58ngs
5. Australia’s two biggest states have abandoned COVID zero, but it’s still a long path to freedom
   https://www.abc.net.au/news/2021-09-02/victoria-and-nsw-abandon-covid-zero-analysis/100426124
6. NZ Delta case ‘originated in NSW’: Ardern
   https://www.smh.com.au/world/oceania/delta-confirmed-as-new-zealand-starts-strict-nationwide-lockdown-20210818-p58jo7.html
7. Disturbances in sleep, circadian rhythms and daytime functioning in relation to coronavirus infection and Long-COVID – A multinational ICOSS study
   https://onlinelibrary.wiley.com/doi/epdf/10.1111/jsr.13542
8. A computational biologist weighs in on Omicron, the future of vaccines, and the CDC’s variant forecast
   https://www.statnews.com/2021/12/22/a-computational-biologist-weighs-in-on-omicron-the-future-of-vaccines-and-the-cdcs-variant-forecast/
9. A clinical case definition of post-COVID-19 condition by a Delphi consensus
   https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00703-9/fulltext
10. SARS-CoV-2 vaccination induces immunological memory able to cross-recognize variants from Alpha to Omicron
    https://www.biorxiv.org/content/10.1101/2021.12.28.474333v1
11. HOW SEVERE ARE OMICRON INFECTIONS?
    https://www.nature.com/articles/d41586-021-03794-8
12. SARS-CoV-2 variants of concern and variants under investigation in England
    https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1043807/technical-briefing-33.pdf
13. Assessing the age specificity of infection fatality rates for COVID-19: systematic review, meta-analysis, and public policy implications
    https://link.springer.com/article/10.1007%2Fs10654-020-00698-1
14. SARS-CoV-2 variants of concern and variants under investigation in England Technical briefing: Update on hospitalisation and vaccine effectiveness for Omicron VOC-21NOV-01 (B.1.1.529)
    https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1044481/Technical-Briefing-31-Dec-2021-Omicron_severity_update.pdf
15. Attenuated fusogenicity and pathogenicity of SARS-CoV-2 Omicron variant
    https://drive.google.com/file/d/1rhCazFav1pokFKmsZI5_oqIeH9ofFckR/view
16. Immune boosting by B.1.1.529 (Omicron) depends on previous SARS-CoV-2 exposure
    https://www.science.org/doi/epdf/10.1126/science.abq1841