Lead vaccines: answers needed

As lead vaccines announce good results and intentions to register for fast-tracked safety authorisation in EU and the US, immunologist Byram Bridle, reminds us of questions that they will need to answer:

Dr. Byram Bridle, PhD, Associate Professor of Viral Immunology, University of Guelph, Ontario, Canada

  1. How many of the total study subjects are being reported on? Partial results can range from being representative of the entire data set to being biased.
  2. How many study subjects had detectable immune responses and what was the magnitude?
  3. Were there antibody responses in the respiratory tract, which is where SARS-CoV-2 infects, and did these antibodies efficiently neutralize the virus?
  4. Were SARS-CoV-2-specific T cells induced? A balanced anti-viral response should include antibodies to prevent infection and T cells to kill viruses that get past the antibody barrier.
  5. Did the immune responses have a ‘Th1’ or ‘Th2’ bias? The former type of immune response is optimal against viruses, the latter is usually sub-optimal and sometimes even dangerous in the context of respiratory viral infections.
  6. Did the vaccine confer long-term immunological memory? A prophylactic vaccine may be useless without this. If immunological memory is short-lived, vaccinated individuals could become susceptible to infection before enough people are immunized to achieve ‘herd immunity’. Another term for this is ‘duration of immunity’ (i.e. how long does immunological protection last?)
  7. How did the vaccine perform in senescent animals and/or elderly humans? Those most in need of protection against COVID-19 are the elderly and immunocompromised.
  8. How was safety assessed and what were the results?
  9. Have the results been published for review by other scientists? If not, when? It is recommended to publish in open-access journals, which are available to the public. Comments merely reflect opinions unless there are validated data to back them up.
  10. Related to #6 above, what is the plan to manufacture and roll-out enough vaccine doses to achieve herd immunity in any given country? What is the realistic timeline for this? If >1 year, there is no way to know if COVID-19 vaccines will confer protection for this long because they didn’t exist one year ago. The development of every historical vaccine took >4 years, so there were years-worth of ‘duration of immunity’ data. For example, optimistic projections suggest ~1 billion doses might be possible by the end of 2021, but for two-dose regimens, that means only 500 million people could potentially be vaccinated in just over one year. With the global population at 7.8 billion people, that represents only 6% of the world’s population. The lowest estimate to achieve herd immunity is 60%.
  11. How will equitable distribution of vaccines be accomplished? For example, pre-order waiting lists seem to be dominated by developed countries; are any developing countries on these waiting lists?
  12. What is the cost of a full vaccine regimen going to be? Is it affordable for developing countries? Some epidemiologists have predicted that efficient roll-out of vaccines to developing countries will require the price to be <$6 US.
  13. Storage conditions for vaccines could impact distribution and market competitiveness. What data are available to support the claimed storage conditions? For example, the default storage temperature for RNA in research laboratories is -80o This is based on a plethora of scientific evidence that RNA is more stable at this temperature compared to -20oC.

An uncompromising expression of the Covid-skeptic position

Even our jaws dropped at this compelling, powerful, uncompromising statement from a Canadian doctor to the Edmonton City Council Community and Public Services Committe.

Hodkinson is the CEO of Western Medical Assessments, and has been the company’s medical director for over 20 years. He received his general medical degrees from Cambridge University in the U.K., and then became a Royal College certified pathologist in Canada (FRCPC) following a residency in Vancouver.

He also taught at the University of Alberta and runs MutantDx, a molecular diagnostics company in North Carolina.

Dr Hodkinson – Canada

That time when no one noticed Covid19

A study shows a ‘peak’ of Covid19 cases in Italy in September 2019, and no one had noticed.

This hints that Covid19 was circulating even earlier, as the study used blood samples from a lung cancer patient screening trial that had begun in September 2019.

This study shows an unexpected very early circulation of SARS-CoV-2 among asymptomatic individuals in Italy several months before the first patient was identified, and clarifies the onset and spread of the coronavirus disease 2019 (COVID-19) pandemic. Finding SARS-CoV-2 antibodies in asymptomatic people before the COVID-19 outbreak in Italy may reshape the history of pandemic.

https://journals.sagepub.com/doi/10.1177/0300891620974755

Immunologist cautions on lead vaccines

17 November 2020

Byram Bridle, a viral immunologist at the University of Guelph, cautions New Zealanders that the lead vaccines against Covid19 may not be the solution they are expecting to end its isolation under the elimination strategy.

The main points of his caution are:

  1. NZ will have to wait at least two years before the Pfizer vaccine is available, because it is in strict isolation and low on the priority list for the 500m doses available in 2021.
  2. Not enough data has been released to know whether the vaccine prevents or weakens the symptoms of Covid19, or how long the protection will last.
  3. The safety data will be incomplete if it is approved for use next year, so monitoring will need to be carried out on vaccinated people for some years.
  4. The Pfizer data has not been rigorously peer-reviewed.
  5. There is no available data on the qualitative nature of the immune response. Vaccines like this can be misinterpreted by the immune system as an extracellular pathogen, which can cause them to respond poorly to natural infections with future coronaviruses.

“Pfizer’s vaccine is a RNA-vectored vaccine. This technology is relatively new and has not been approved for clinical use before. The company has been able to move surprisingly fast. If the recent data is indicative of what data from the rest of the trial will look like, there is a good chance the vaccine could receive emergency approval by early in 2021.

However, there are many nuances…”

Insufficient public data

“The study is only partially complete. There exists the possibility that the final data set will fail to secure regulatory approval (but it looks like they may be on track).

Data that accompanied the Pfizer press release was extremely superficial and, therefore, difficult to interpret. Data being collected for the Pfizer study cannot accurately be commented on until it undergoes rigorous peer review for publication in a good quality scientific journal.”

Effectiveness of protection

“90% effectiveness sounds surprisingly high. But we have no idea what the demographics look like. Although they opened the trial to high-risk people, we have no idea who contracted COVID-19. As an extreme example, if all the vaccinated volunteers that got COVID-19 were elderly and that number was not significantly different from the elderly among the non-vaccinated volunteers that got COVID-19, that would tell us that the vaccine does not work in those who need it most.

Most of the cases of COVID-19 in the study were presumably mild to moderate since no hospitalizations or deaths were reported, so we don’t know how protective the vaccine will be for those who are susceptible to severe cases.

There is no data regarding immunological memory, which is the entire point of a vaccine. If the memory response is weak or wanes too quickly, people will not be protected over the long term. This would be a fatal flaw because the global roll-out of a vaccine will take a very long time.

Pfizer hasn’t stated what the qualitative nature of the vaccine-induced immune response is. Sub-unit vaccines like theirs have been known to be misinterpreted by the immune system as being an extracellular pathogen. If that is the case, people who receive this vaccine might have a bias imprinted on their immune system that could cause them to respond to natural infections with future coronaviruses in a sub-par fashion.”

Two dose vaccine.

  • “It can be hard to get people back for a second dose. It is probably achievable in urban centres but could be hard to get the same people back 21 days later in remote and/or difficult-to-access places, especially in developing countries.
  • A vaccine that needs two doses is arguably a ‘weak’ vaccine. For this vaccine, it will take 28 days to build up sufficient protection. So there will be a one-month window during which people will remain susceptible. A better quality, single-dose vaccine could probably reduce this to 10-14 days.
  • Fewer than 500 million people could be vaccinated within a year of the vaccine being approved. The company is going to try to stockpile 50 million vaccines this year in anticipation of the vaccine being approved, and they optimistically predict that they can make 1.3 billion doses by the end of 2021. This sounds like a lot, but a two-dose regimen cuts the number of people that can be immunized in half. The person to get the 500 millionth dose will have to wait a year compared to the person who gets the first one. Some will wonder why some people get two doses while they get none. The vaccine won’t be protective unless two doses are given.”

Roll out internationally

“What about the rest of the population? As many of us have been predicting, it could take years to roll out these vaccines. Approval of a vaccine doesn’t help anyone; what matters is when it has been administered and sufficient time has passed for the immune system to respond. Of course, where in this very long timeline for the roll-out will countries that have used strict isolation to control their cases be (arguably, low on the priority list). Pfizer’s press release is essentially saying that everyone beyond the first half-million people will have to wait over 1 year. Presumably, it also means that people beyond the first billion or so may have to wait over 2 years.”

Long term safety

“Long-term safety in people is inferred based on animal models (such as rodents) that have shorter lifespans. Usually, clinical trials are done sequentially and span quite a few years. So acute and some long-term (i.e. 4 or more years) safety data would be in-hand. With the different trial stages overlapping and being run faster than normal, we will likely have less than a year’s-worth of safety data. Ultimately, the only way to be completely sure about long-term (i.e. beyond the duration of the clinical trial phase) safety in people is to monitor vaccinated people for a long period of time after the roll-out. Things like long-term kidney damage, etc. can often (but not always) be predicted/ruled out by things like blood chemistry within the acute stages.”

/ends

No appreciable risk of Covid19 infection from close contact with children

Another piece of evidence against lockdowns; research shows close contact with children under 11 has no increased risk of Covid19 infection, close contact with those 12-18 has a small increased risk of infection, while there was no impact on outcomes of being infected with Covid19. As a bonus, closeness to children reduces non-Covid19 deaths….

Working on behalf of NHS England, we conducted a population-based cohort study using primary care data and pseudonymously-linked hospital and intensive care admissions, and death records, from patients registered in general practices representing 40% of England. Using multivariable Cox regression, we calculated fully-adjusted hazard ratios (HR) of outcomes from 1st February-3rd August 2020 comparing adults living with and without children in the household.

Findings Among 9,157,814 adults ≤65 years, living with children 0-11 years was not associated with increased risks of recorded SARS-CoV-2 infection, COVID-19 related hospital or ICU admission but was associated with reduced risk of COVID-19 death (HR 0.75, 95%CI 0.62-0.92). Living with children aged 12-18 years was associated with a small increased risk of recorded SARS-CoV-2 infection (HR 1.08, 95%CI 1.03-1.13), but not associated with other COVID-19 outcomes. Living with children of any age was also associated with lower risk of dying from non-COVID-19 causes. Among 2,567,671 adults >65 years there was no association between living with children and outcomes related to SARS-CoV-2. We observed no consistent changes in risk following school closure.

Interpretation For adults living with children there is no evidence of an increased risk of severe COVID-19 outcomes. These findings have implications for determining the benefit-harm balance of children attending school in the COVID-19 pandemic.

Funding This work was supported by the Medical Research Council MR/V015737/1.

Evidence before this study We searched MEDLINE on 19th October 2020 for population-based epidemiological studies comparing the risk of SARS-CoV-2 infection and COVID-19 disease in people living with and without children. We searched for articles published in 2020, with abstracts available, and terms “(children or parents or dependants) AND (COVID or SARS-CoV-2 or coronavirus) AND (rate or hazard or odds or risk), in the title, abstract or keywords. 244 papers were identified for screening but none were relevant. One additional study in preprint was identified on medRxiv and found a reduced risk of hospitalisation for COVID-19 and a positive SARS-CoV-2 infection among adult healthcare workers living with children.

Added value of this study This is the first population-based study to investigate whether the risk of recorded SARS-CoV-2 infection and severe outcomes from COVID-19 differ between adults living in households with and without school-aged children during the UK pandemic. Our findings show that for adults living with children there is no evidence of an increased risk of severe COVID-19 outcomes although there may be a slightly increased risk of recorded SARS-CoV-2 infection for working-age adults living with children aged 12 to 18 years. Working-age adults living with children 0 to 11 years have a lower risk of death from COVID-19 compared to adults living without children, with the effect size being comparable to their lower risk of death from any cause. We observed no consistent changes in risk of recorded SARS-CoV-2 infection and severe outcomes from COVID-19 comparing periods before and after school closure.

Implications of all the available evidence Our results demonstrate no evidence of serious harms from COVID-19 to adults in close contact with children, compared to those living in households without children. This has implications for determining the benefit-harm balance of children attending school in the COVID-19 pandemic.

 

 

https://www.medrxiv.org/content/10.1101/2020.11.01.20222315v1

Children in more danger from lockdown than Covid19

“…benefits [of lockdown], however, are overshadowed by the negative consequences of the lockdown. First and foremost is the direct impact on their health. Emergency departments in the UK experienced unprecedented reductions of >50% in attendances during lockdown. [8] In Scotland, children’s emergency department attendances fell proportionally more than any other age-group.  This raises concerns that children with critical illnesses were not accessing health services on time and, therefore, suffering potentially avoidable harm.

 

60% of paediatricians responded within 7 days and, and 241 (32%) of 752 emergency department paediatricians had witnessed delayed presentations. Free text responses revealed diabetes mellitus (new diagnosis/diabetic ketoacidosis) as by far the most common delayed presentation, followed by delayed presentations of sepsis and new cancer diagnoses.

 

There were also nine deaths, resulting mainly from sepsis and malignancy, where delayed presentation was considered by the reporting paediatrician to be a significant contributing factor – higher than the total number of childhood covid-19 deaths reported over the same period in England.

Lockdown measures reduced the risk of covid-19, but had unintended consequences for children

Sunetra Gupta on unprofessional conduct of pro-lockdown scientists

Sunetra Gupta, founding signatory of the Great Barrington Declaration, wrote for the Daily Mail. Here is an edited set of excerpts.

I was utterly unprepared for the onslaught of insults, personal criticism, intimidation and threats that met our proposal. The level of vitriol and hostility, not just from members of the public online but from journalists and academics, has horrified me.

… Covid-19 is not a political phenomenon. It is a public health issue — indeed, it is one so serious that the response to it has already led to a humanitarian crisis. So I have been aghast to see a political rift open up, with outright abuse meted out to those who, like me, question the orthodoxy.

That is why I have found it so frustrating how, in recent weeks, proponents of lockdown policies have seemed intent on shutting down debate rather than promoting reasoned discussion.

 

It is perplexing to me that so many refuse even to consider the potential benefits of allowing non-vulnerable citizens, such as the young, to go about their lives and risk infection, when in doing so they would build up herd immunity and thereby protect the lives of vulnerable citizens.

 

Yet rather than engage in serious, rational discussion with us, our critics have dismissed our ideas as ‘pixie dust’ and ‘wishful thinking’.

This refusal to cherish the value of the scientific method strikes at the heart of everything I, as a scientist, hold dear. To me, the reasoned exchange of ideas is the basis of civilised society.

 

So I was left stunned after being invited on to a mid-morning radio programme recently, only for a producer to warn me minutes before we went on air that I was not to mention the Great Barrington Declaration. The producer repeated the warning and indicated that this was an instruction from a senior broadcasting executive.

I demanded an explanation and, with seconds to go, was told that the public wouldn’t be familiar with the meaning of the phrase ‘Great Barrington Declaration’.

 

And this was not an isolated experience. A few days later, another national radio station approached my office to set up an interview, then withdrew the invitation. They felt, on reflection, that giving airtime to me would ‘not be in the national interest’.

 

But the Great Barrington Declaration represents a heartfelt attempt by a group of academics with decades of experience in this field to limit the harm of lockdown. I cannot conceive how anyone can construe this as ‘against the national interest’.

 

Moreover, matters certainly are not helped by outlets such as The Guardian, which has repeatedly published opinion pieces making factually incorrect and scientifically flawed statements, as well as borderline defamatory comments about me, while refusing to give our side of the debate an opportunity to present our view.

 

I am surprised, given the importance of the issues at stake — not least the principle of fair, balanced journalism — that The Guardian would not want to present all the evidence to its readers. After all, how else are we to encourage proper, frank debate about the science?

 

On social media, meanwhile, much of the discourse has lacked any decorum whatsoever.

 

I have all but stopped using Twitter, but I am aware that a number of academics have taken to using it to make personal attacks on my character, while my work is dismissed as ‘pseudo- science’. Depressingly, our critics have also taken to ridiculing the Great Barrington Declaration as ‘fringe’ and ‘dangerous’.

 

But ‘fringe’ is a ridiculous word, implying that only mainstream science matters. If that were the case, science would stagnate. And dismissing us as ‘dangerous’ is equally unhelpful, not least because it is an inflammatory, emotional term charged with implications of irresponsibility. When it is hurled around by people with influence, it becomes toxic.

 

But this pandemic is an international crisis. To shut down the discussion with abuse and smears — that is truly dangerous.

Yet of all the criticisms flung at us, the one I find most upsetting is the accusation that we are indulging in ‘policy-based evidence-making’ — in other words, drumming up facts to fit our ideological agenda.

 

I have been accused of not having the right expertise, of being a ‘theoretical’ epidemiologist with her head in the clouds. In fact, within my research group, we have a thriving laboratory that was one of the first to develop an antibody test for the coronavirus.

Clearly, none of us anticipated such a vitriolic response.

 

The abuse that has followed has been nothing short of shameful.

But rest assured. Whatever they throw at us, it won’t do anything to sway me — or my colleagues — from the principles that sit behind what we wrote.

Professor Sunetra Gupta is an infectious disease epidemiologist and a professor of theoretical epidemiology at the Department of Zoology, University of Oxford.

https://www.dailymail.co.uk/debate/article-8899277/Professor-Sunetra-Gupta-reveals-crisis-ruthlessly-weaponised.html

Coronavirus T-cell immunity lasts at least six months even when antibodies are undetectable

There was widespread alarmist media coverage in July and again in October of research by Kings College and Imperial College respectively of research showing anti-body reaction to covid19 disappeared within as short as time as a few weeks (average 2-3 months).

Both researchers obliged media by saying the results showed that  controversial ‘herd immunity’ concept could not work.

But a new study by University of Birmingham and Public Health England, shows memory T-cells were present in all 100 asymptomatic non-hospitalised patients they tested, meaning coronavirus patients have cellular immunity for at least six months after infection even when antibodies are undetectable.

It suggests that more people may have had Covid than previously thought but have lost their antibody response, meaning it would not show up in surveillance testing.

Previous studies have shown that Sars – a very similar virus to coronavirus – can induce a T-cell response that lasts 10 years, but it was unknown whether a cellular response also happened in Covid.

Dr Shamez Ladhani, consultant epidemiologist at PHE and the study’s author, said: “Cellular immunity is a complex but potentially very significant piece of the Covid-19 puzzle.

“Early results show that T-cell responses may outlast the initial antibody response, which could have a significant impact on Covid vaccine development and immunity research.”

Professor Paul Moss, the UK Coronavirus Immunology Consortium lead, of the University of Birmingham, said it was the first study in the world “to show robust cellular immunity remains at six months after infection in individuals who experienced either mild/moderate or asymptomatic Covid-19. Six months is an early time point, and cells can live for a very long time.”

A devastating critique of the ten worst data failures of Covid19

Data has been the most disappointing factor about humanity’s response to Covid19.

It has been faulty, incomplete, inconsistent, skewed by design, and often, invented (ie. models).

It seems like most of the disputes over how dangerous Covid19 is, and what to do about it, hinge on data that is unreliable. Our ability to interrogate data far outstrips the quality of the data.

It’s not been a flattering picture for the future, of the capabilities of our modern age.
https://www.spectator.co.uk/…/The-ten-worst-Covid-data-fail…

Throughout the pandemic, the government and its scientific advisers have made constant predictions, projections and illustrations regarding the behaviour of Covid-19. Their figures are never revisited as the Covid narrative unfolds, which means we are not given an idea of the error margin….

Experts changing their minds as facts against Covid19 mount

Abstract

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused the Coronavirus Disease 2019 (COVID-19) worldwide pandemic in 2020. In response, most countries in the world implemented lockdowns, restricting their population’s movements, work, education, gatherings, and general activities in attempt to ‘flatten the curve’ of COVID-19 cases. The public health goal of lockdowns was to save the population from COVID-19 cases and deaths, and to prevent overwhelming health care systems with COVID-19 patients. In this narrative review I explain why I changed my mind about supporting lockdowns. First, I explain how the initial modeling predictions induced fear and crowd-effects [i.e., groupthink]. Second, I summarize important information that has emerged relevant to the modeling, including about infection fatality rate, high-risk groups, herd immunity thresholds, and exit strategies. Third, I describe how reality started sinking in, with information on significant collateral damage due to the response to the pandemic, and information placing the number of deaths in context and perspective. Fourth, I present a cost-benefit analysis of the response to COVID-19 that finds lockdowns are far more harmful to public health than COVID-19 can be. I close with some suggestions for moving forward.

https://www.preprints.org/manuscript/202010.0330/v1