Friday, 24 July 2020

Vaccines - the next horse in the race

Hot on the heels of my last post, the Oxford group have published the results of their phase 1 and 2 trials on a vaccine against Sars-Cov2-19. They too have been successful in terms of what is expected from a phase 1/2  study; that is to establish if a product is safe enough and effective enough to be worth going on to phase 3 trials which if successful will mean they
Oxford
become widely available to the public.

Summary

They conclude

"A vaccine against SARS-CoV-2 could be used to prevent infection, disease, and death in the global population, with high-risk populations such as hospital workers and older adults (eg, ≥65 years of age) prioritised to receive vaccination. 

...Immunisation with ChAdOx1 nCoV-19 results in rapid induction of both humoral and cellular immune responses against SARS-CoV-2, with increased responses after a second dose. Further clinical studies, including in older adults, should be done with this vaccine."

In other words, it works.

The Vaccine


Their vaccine was different to the RNA virus in the Moderna trial I reported on in the last post. The Moderna RNA vaccine recruits our own capability to make antigens which then triggers an antibody response in the absence of active infection. This vaccine uses harmless viruses which are modified to contain Sars-Cov2-19 spike proteins on their surface and again 'trick' us into generating an immune response to viruses before they arrive and giving us the capability of destroying the Sars-Cov2-19 by recognising its spike protein should we encounter it. 
Spikey proteins

The Oxford vaccine had a head start in that similar techniques had been explored in attempts of develop a vaccine against MERS, that earlier cousin of COVID19 which passed directly from camels to humans, but thankfully (with a mortality of 35%) not from humans to humans. 

The vaccine is called the ChAdOx1 nCov19 vaccine. 

Bit of a mouthful, but Ch because the viral 'vector' has its origin in chimpanzees, Ad because the virus vector used to carry the spike antigen is one of the Adenoviruses, and Ox1 because it is the first vaccine from the Oxford group. nCov19 as the vaccine is directed against the novel Coronavirus '19.

The Trial


They enrolled 1077 healthy volunteers with no health problems and no history or suggestion of previous infection with Sars-Cov2-19 when tested. They were randomised into two groups; one getting the Sars vaccine and the other the vaccine against meningitis. A further small sub group was given a booster dose one month later. The age spread was 18-55 years, similar numbers of both sexes and an average age of 35.

Interestingly only 4% of the volunteers already had antibodies to the virus suggestive of previous asymptomatic infection. Anyone with any viral symptoms since February was excluded.

They describe the effect of injection of 5 x1010 viral particles. Yes, that's the minute scale of viruses; in other words 50,000,000,000 viral particles are injected into the deltoid. The best dose had been calculated from experience with the vaccine against MERS. 

Tolerability


In terms of tolerability, the vaccine was compared to a similar vaccine routinely used against four strains of meningitis and currently offered as routine to teenagers. Side effects, mainly muscle aching, chills, headache and fever were more common after the Sars vaccine than the meningitis vaccine but none were classed as serious, all resolved by day 7 and were reduced by the use of paracetamol. 

Results


Antibodies to the spike protein were generated by day 28 after the vaccine in 91-100% of the volunteers depending on the test used and they were shown to be capable of neutralising Sars-Cov2-19 in further tests -  so, success on that score. Levels of antibody were increased by a booster dose one month late and this second dose was not associated with as many side effects as the first.

Interestingly, cell mediated immunity was rapidly generated in the form of T white blood cells which are able to recognise and importantly remember the viral proteins even without any antibody response. These persisted at 56 days and are likely to continue as they have with other vaccines and infections.

So a 'double whammy' awaits the virus when the volunteers come across it - that will be monitored too. 

What next


These preliminary trial results are good news. They suggest that in the medium term we might reach a situation where there will be no more worry about Sars-Cov2-19. Phew! By then, many people will have acquired immunity naturally, and those at high risk can be immunised.

Phase 3 trials are under way in the UK and abroad, presumably in current hot spots like Brazil where trials will potentially be saving lives while we await the results we hope for but cannot assume. The more common the rates of infection in the trial population, the more accurate the results will be.

Questions.....


What about the aged?

Similar vaccines techniques against influenza have induced a significant immune response in the elderly in small trials. There is hope therefore that ChAdOx1 nCov19 will be effective for the elderly and the next phase will give us the answer to this critical question. Even with senescent immune systems, us oldies continue to have our ways of fighting back!

Availability

It may be that the production lines of these vaccines are worlking away even before the trial results are available. Personally, I consider this a reasonable risk to the public purse given the circumstances.

The 'normal' view has been that any vaccine will not be available until the end of the year at the earliest but the RNA vaccine is simpler to scale up and manufacture than ChAdOx1nCov19. Perhaps they will both have their place for different moments of the pandemic and even in different populations - time will tell.

The winter

By the winter we might be in the middle of a second wave, something that increasing number of authorities are concerned about when indoor life, low temperatures and falling Vitamin D levels all enhance viral activity and given the fact that the virus is still out there causing poorly
managed outbreaks. 

Here in the UK we have a dog's dinner of a testing and tracing system; 'world beating' only in its dogma driven centralisation so as the autumn comes, so it seems very unlikely the virus will be gone as the Autumn heads into winter.

If a second wave does not arrive prior to a vaccine, and damaging restrictions have not been needed, then the place of vaccination might well be more selective. High risk groups the elderly and health and care sector workers - all those identified in the first wave as vulnerable. 

We will also have found out what we are in for in terms of this years flu, and vaccines for this are likely to be rolled out in far greater numbers, 30 million I understand,  as having two outbreaks at once would be really tough for us all. 

The future

Recent XR protest Tavistock
One added advantage of the vaccine story is that teams and techniques will be more ready to react when the next inevitable spillover of pathogens from the natural world comes along. (Unless of course, we learn to live with our remaining natural habitats and treat them with due care) For those vaccinated or infected, some cross reactivity with the next novel coronavirus will be likely, though not guaranteed.

It would be great to have ways of testing T cell immunity more widely, but the tests are too expensive for this right now; perhaps this will change. If so it would vastly improve the way we can track any further pandemics and clear the fog surrounding what herd immunity means in reality.


Whatever happens, we will have to pick up the debris and so many challenges remain in terms of the many faceted threats we all face. The worst of the pandemic will fade into the past, but will still leave us with a future as threatening and change as urgent as ever.  

The failure of global politics to get to grips with reality, mitigated somewhat by the many new networks formed in the scientific world, still leaves some very inadequate leaders in power here and elsewhere. International co-operation, so essential for the future, looks shakier than ever.

The 'old abnormal' is simply not survivable.

Wednesday, 15 July 2020

Vaccine against Sars-Cov2-19 - over the first hurdle!

It may seem that things have gone very quiet on the vaccine front, but this has not been the case. 23 vaccine candidates have entered clinical trials in the five months since the pandemic arrived, and now the first encouraging report has been published.

Antibodies vs Sars-Cov2-19

It was with incredible speed that phase 1 trials to establish safety, dosage and formulation were started. The usual time from identification of a viral genome to phase 1 trial is 3-9 years. The first vaccination in this trial was given after 66 days on the 16th March.

The trial is called the Moderna trial, after the biotech company behind it, in co-operation with the National Institute of Health in the USA and took place in Seattle and Atlanta. 

The researchers have reported the preliminary results on the 47 subjects who were vaccinated back in March and the results seem very encouraging.

The trial


The 45 people in the trials were given two vaccinations 28 days apart, and three different doses were trialled. The vaccine consists of altered viral RNA coding for a protein on the infamous spike of the Sars-Cov2-19. 

It is wrapped up in a lipid nanoparticle, rather like a microscopic envelope, and injected into the deltoid muscle whose genetic machinery then generates a protein antigen similar to one of the proteins on the spike of Sars-Cov2-19. The immune system then generates the antibodies which are active against the virus. Clever stuff!



What happened?


The participants all generated enough antibodies to suggest effectiveness against COVID19, with the middle dose achieving the best balance between side effects and effectiveness. Of course, they don't know how long this will last, but 57 days later, at the time of publication, the levels are still adequate for protection - so far so good! 

Side effects were common, with fatigue and chills affective 80%, headache in 60% and muscle pain in half of those given the middle dose, but all were reported as mild or moderate in severity and transient.

Further reports are due on the effects in the crucial over 55 age group and of course, how long the antibody response persists. There is a larger second phase trial proceeding as we speak and a larger phase three trial to start at the end of July.  

Naturally, the trial volunteers simply have the treatment and go away, to be followed up with blood tests and their side effects monitored, so time will tell. 
 
The researchers conclude;

The mRNA-1273 vaccine induced anti–SARS-CoV-2 immune responses in all participants, and no trial-limiting safety concerns were identified. These findings support further development of this vaccine.

What next?


There will be more reports from this trial as time goes by, in particular with older participants, and of how the antibody response persists.
 
Phase 2 will be to look at the effectiveness on a larger group of a few hundred individuals including the more at risk older groups. Phase three will then look at a larger population based study of the finished product in what are usually randomised controlled trials of effectiveness in the real world.

I'm curious to know how and indeed, where this phase 3 trial will be performed. Brazil looks the best place right now. This is because the more people vulnerable to the virus, the more the benefits, or otherwise, of the vaccine will be evident.  There have been calls to intentionally infect volunteers to test the effectiveness of the vaccine directly.

Potentially, the vaccine could be ready in 6-9 months. Moderna (naturally) are optimistic stating that: "the Company remains on track to be able to deliver approximately 500 million doses per year, and possibly up to 1 billion doses per year, beginning in 2021."


Of course, by then we will be heading into the new year, which in terms of the pandemic, and this difficult year, seems a long time away. By then we will have a good idea how the virus and us, its hosts, are behaving in the winter of the northern hemisphere with all the challenges that will bring. (I'm keeping my fingers crossed that we are lucky with flu this year.)

We must not underestimate the many significant hurdles to be overcome before any of us call our GP or the chemist for a coronavirus jab, but the first hurdle has been overcome. I feel sure that there will be a flurry of these papers soon with more results on the way.

We with the publication of this paper, we are one step nearer to a vaccine which will signal hope for effective prevention against COVID19.







Thursday, 9 July 2020

Herd Immunity? It might be nearer than we think.

You might well be wondering what is going on with herd immunity. I know I am. 

Despite the ravaging of the worlds population and its brittle economies by Sars-Cov2-19, herd immunity seems to remain so far away as to make any realist wonder it if will ever be achieved.

It might be that lockdown and changes in our behaviour are having such a dramatic viral-avoiding effect that less that 10% of the population have positive antibody tests. In Spain, so hard hit early in the pandemic, antibodies are present in only 5% of the population, 
leading commentators to again state its achievement through policy is not only unethical, but unachievable.

Even in Sweden with their more relaxed approach to the pandemic and higher levels of mortality, the number of people joining the 'herd', that is those with acquired immunity measured by the presence of antibodies, seems stuck at 7.3% at most. It is fair to say as things stand it seems we will never reach herd immunity.

Over here I have called our tardy response to the pandemic "Herd Immunity by the back door" it now seems the back door is only very slightly open and herd immunity as far beyond the horizon as ever.

So, might we be barking up the wrong tree. Or indeed just one branch? Are we ignoring other branches we could equally well be barking up?

Our guided missiles


If you like, think of antibodies as molecular guided missiles, prepared and waiting for invaders they can recognise, at least until they get rusty and melt away, or the invaders get new 
Antibodies
disguises. 
 

In terms of herd immunity, we have understandably focussed entirely on the development of these antibodies to the virus, something which usually happens after significant clinical infections or vaccination. This is called "Acquired Immunity" and is generated by B Cells - "B" as they come from the Bone marrow.

Fair enough, but to me something seems amiss. Lockdown has been a severe experience, yet there has still been plenty of opportunity for spread of the virus beyond the number of people developing immunity as measured by positive antibody tests.

One factor might be that immunity measured in this way is short lived. A small Chinese study demonstrated the disappearance of antibodies in 40% of infected people without symptoms and even in 13% of those with symptoms. Unsurprisingly, the more severe the infection, the more antibodies you develop and the better your defence next time.

That might be one reason why the numbers of people with positive antibody tests are lower than expected. Another more positive reason might be adequate immunity resulting from our immune cells which act without making antibodies.

Immune Memory


Evidence from Sweden, suggests there may be more to COVID19 immunity than meets the eye. They found that many people who have been in contact with known cases, and even random blood donors, have developed specific Memory T cells which target the virus despite being antibody negative.

This happens when we create a certain type of white cell called T-cells. "T" because they derive from the little known and vastly under appreciated Thymus gland, quietly tucked away behind the thyroid gland in your neck. There are different types of T cells - here they looked at T
Thymus Gland
Memory cells, which are capable of remembering the proteins of the surface of previous viral or bacterial infections and so are enabled to react and defend us in the event of re-exposure.

It should be noted that the Thymus shrinks through life and as immunosenecense (ageing of the immune system) sets in it means there are less of these memory cells available. This mechanism therefore becomes less less effective as we age and is reflected in the increased impact of viral infections in the elderly.

The researchers discovered that these Memory T cells are able to recognise proteins unique to Sars-Cov2-19 and so organise the local resistance and destruction of the viruses, and remember doing so without the need for antibodies.

Further, it seems that these wonderful cells can recognise proteins on the surface of viruses due to past infections with similar viruses. In this case that means the more severe, though less transmissible Sars-Cov1, or even far more benign coronaviruses causing colds. This might have many benefits.

Potential Benefits  


In essence, the immune system of many people who come across the virus is able to defeat it before it has a chance to do any damage or create significant symptoms. Either no symptoms at all or perhaps a soon forgotten day of feeling tired or lethargic. The virus is beaten off before it starts large scale replication or does enough damage to stimulate the immune response involving the generation of antibodies.

Further, Memory T cells do just that; they remember, and it seems they can last for years. We know this after Sars-Cov1. People infected 17 years ago still have
T Cell
functioning populations of these Memory T cells which can recognise that virus but also similar proteins on Sars-Cov2-19 and thus confers what the authors term "robust cross-reactivity" active against developing COVID19. Some of these target proteins are essential for Sars-Cov2-19 to take hold and replicate.

In other words, if you had Sars-Cov1, it is possible you are protected against Sars-Cov-2-19. 

Better still, though the numbers studied are small, the researches found Memory T cells in 50% of blood donors which had activity against some of the Sars-Cov2-19 proteins. This is despite the donors never having come across it or Sars-Cov1 or 2. This suggests that some of this pre-programmed defence against Sars-Cov2-19 might had been acquired after infection with common colds caused by betacoronaviruses, benign relatives of our most recent viral visitor. 

Wow! 

This might also partially explain why children and the young are not generally severely affected by the virus if at all; they come across lots of colds caused by coronaviruses and are thus, to some extent at least - 'pre-armed" with relevant Memory T cells and protected. The memory might be less clear than for those infected with SARS first time round, but is is nonetheless significant. 

Good News


Although the researchers justifiably call for more research, these findings are good news.

In short it suggests:
  • Many people infected have immunity despite not having antibodies.
  • Many people have some immunity against Sars-Cov2-19 due to previous mild viral infections.
  • Herd immunity as measured by antibody tests might never be reached
  • We might be closer to herd immunity that we think
This might make little difference at the policy level; it still remains that many of us have weakened immune systems due to age, disease, lifestyle or low Vitamin D and are vulnerable. 

However, I am beginning to wonder as to the use of "game changing" antibody tests. A positive test will tell us if we have antibodies and so have been infected, but will still miss many who have had the infection and done well. A negative test might suggest we are vulnerable, or for the same reason, it might not. They would tell us how many people have developed antibodies - that is only a part of the picture.

Testing for the presence of specific Memory T cells is too tricky for widespread use.

However, it might relieve us of the sinking feeling when we considered that well over 90% of the population don't have antibodies to Sars-Cov2-19 and are thus thought to be vulnerable. This research suggests this might not be the case at all and we might have far more immunity than we thought.

How close are we to herd immunity? We don't know, but we are likely to be closer than we think.

Our wonderful immune system


Our immune system is a thing of wonder. Its complexities are slowly unravelling and this is being accelerated by the pandemic. There are many other facets to our immune defences against developing COVID19. These include well designed interfaces with the outside world (skin, respiratory and digestive systems, etc), barriers such as mucus production, our own production system of antibiotic molecules as well as other many other active immune cells including phagocytes and macrophages.

So Memory T cells are but one branch of the tree of our immune system, but the increasing knowledge of how they help us survive the microbiological barrage from the outside world is a wonder to behold.

I have been on my own journey with this and the more I learn, the more I realise how little I knew, and how much more is to be discovered. More on this later.....