In an article in Quadrant Online in January this year, twelve months into a pandemic with a level of devastation unknown to our generation, I described Australia as an island nation, isolated in an artificial and unstable bubble from a sea of COVID-19 causing 15,000 deaths across the world each day. At that time Australia was recording a daily count of ten new cases of COVID infection, with only three deaths in the preceding three months. Yet at least the first half of the nightly news was all COVID-19 while the “experts” who filled our screens found the post-truth world a comfort zone.
The political imperative was zero tolerance for COVID-19, which, taken to extremes with lockdowns, gave political capital but at a cost of compromising broader health challenges and considerable economic damage. The plan appeared to be maintenance of a COVID-free environment within controlled borders, backed by strict hotel quarantine and public health principles, until the pandemic has faded, or to open the borders on the achievement of immunity via the vaccine roll-out that was about to be launched. The strength of confidence in this outcome within the political-medical-media “elite” was such that science regarding additional strategies was remarkably, and without precedent in modern times, replaced by an ideology reminiscent of pandemics of earlier times. The extreme of this arrogance was the rejection of several cheap and safe repositioned drugs, notably hydroxychloroquine (HCQ) and ivermectin (IVM), both of which have been shown to reduce admission to hospital and death by around 60 to 70 per cent. The role of Big Pharma in denigrating these drugs and supporting the political mantra at a time when they were taking hundreds of millions of dollars in government grants to produce patented and high-profit drugs for early COVID-19 treatment was indefensible.
The gist of my January article was that pandemics rarely fade; that COVID-19, an infection of the airways mucosal compartment, will not produce sterilising immunity; and nor will injected vaccines. While vaccines are the backbone of long-term management, current examples are essentially experimental, with only months of study. There was still much to be learnt about efficacy and safety. The influenza vaccine was offered as a model, given similarities between influenza and COVID-19. These comments were not what politicians wanted, and not what most “experts” advised.
Eighteen months into the pandemic, where do we stand in terms of clinical progress and the impact of the vaccines? Perhaps the best way to examine current thoughts is in terms of a five-step management program to take Australia through the pandemic:
♦ Develop a vaccination program using the best available vaccine, with the objective of immunising 80 per cent of the population.
♦ Initiate a vaccine development program based on annual boosters to cover emerging mutants, and to re-stimulate waned immunity.
♦Maintain, at the highest level, community testing, tracing and quarantine.
♦ Identify and quarantine all high-risk subjects arriving from countries with residual COVID-19.
♦ Deliver prophylactic and early drug treatment, where appropriate, using HCQ or IVM, as backup and supplement to the vaccine program.
I will restrict comment to my area of expertise—immunology and early clinical management—while recognising the importance of public health involvement in community and quarantine control, and the commercial contribution to maintaining antigenically appropriate vaccine production.
The pandemic and the impact of vaccines
First, a comment on the progress of the pandemic, its relevance to Australia, and evidence that vaccination can influence disease patterns. By mid-May 2021, 165 million cases of COVID-19 had been registered worldwide, with 3.5 million deaths. This is, of course, an under-estimate, perhaps by a large figure, especially in developing countries with limited diagnostic and medical facilities. The pandemic has been progressing for nearly eighteen months, with a background death rate of around 5000 to 6000 per day, and occurring in up to three waves: August 2020, November–February 2020-21, and April 2021. Every country has its own profile.
The current wave has been devastating in India, which was little affected earlier. In April and early May 2021, over 4000 new cases a day were recorded in India, flooding health services that could not cope with even the most basic of services in many areas. These desperate situations, highlighted in the Australian media, as many Indian-Australian citizens strove to return to Australia, were typical of many countries where public health facilities were unable to cope with the pressure of infection.
More threatening to Australia is Papua New Guinea, due to our porous northern border. Few cases were recorded before March 2021, but in the next two months the pandemic exploded out of control, with under-recording of cases and deaths. The official figure of 15,000 cases with 150 deaths is inaccurate, with a low testing rate. Facilities are inadequate, with a negligible vaccine program.
If we look at three countries with previous high rates of infection (the UK, US and Israel) with more than 40 per cent of the population fully vaccinated, very little third wave was observed. This is consistent with a combined effect of vaccination and a high level of post-infection immunity, further supported by a low observed “breakthrough” infection rate, recorded in the US at 0.15 per cent.
A large study in US aged-care homes compared vaccinated and non-vaccinated subjects, to show low but similar infection rates. Although explained as evidence for herd immunity in an isolated population, it is equally possible the data reflected poor protection due to immune senescence. An overview of all post-vaccination data suggests protection against severe disease, with around 70 to 80 per cent protection against all episodes, and a shift towards asymptomatic infection. Around 25 per cent of breakthrough infections are asymptomatic.
All vaccines have shown less activity against various mutants, and in some studies breakthrough infections are mainly caused by variant strains of virus. Follow-up studies are too short to estimate duration of protection, but the value of the influenza model is gaining ground.
How safe are the vaccines?
The key question is not whether the vaccines work, or even how well they work. It is whether they are safe. Pandemics call for decisions to be made quickly. Vaccines are usually developed over a decade. The Ebola vaccine development time of four years was considered hasty. The COVID-19 vaccines, after two months clinical study, were available for roll-out in one year. This was unprecedented in terms of speed of development and regulatory assessment. The Pfizer, Moderna and AstraZeneca (AZ) vaccines used novel technology. The “vaccine” was genetic material, encoding information that instructed cells taking up the mRNA molecules (Pfizer, Moderna) or DNA vector (AZ), to make the “spike protein” antigen, the virus anchor that binds to the ACE-2 receptor to allow viral cell entry.
Both the mRNA and DNA vector delivery systems had a shaky past—no previous vaccine using these technologies had survived limited clinical study. No evidence has shown these “clever” vaccines to be better than traditional “antigen” vaccines, where a minute amount of antigen stimulates immunity in local lymph nodes. The concern with the genetic vaccines is that they instruct production of an unknown amount of spike protein throughout the body. Interaction between uncontrolled spike protein production and existing immunity and a link to systemic “acute inflammatory” reactions has become a focus of attention in the northern hemisphere. These acute responses appear to be the targeting of cells expressing the spike protein on their surface, by sensitised T cells, or an outcome of antibody/antigen interaction.
The Australian public’s attention to adverse events came not with “systemic inflammation” due to uncontrolled spike protein production, but rather with life-threatening clots associated with a low platelet count. This is due to the DNA and mRNA carrying a net negative charge, creating an identical syndrome to one seen rarely with prolonged therapeutic use of heparin—again due to its negative charge. This adverse event changed vaccine allocation in Australia, with those aged under fifty offered the Pfizer (mRNA) vaccine and those aged over fifty, the AZ (DNA vector) vaccine. It is hard to follow the logic of this decision, as both the mRNA and the DNA vector vaccines can cause clots and at an average age a little over fifty, indicating older subjects have a similar chance of getting a thrombotic complication. A cynic may suggest the real reason for change is the high rate of reported deaths in the elderly from mRNA vaccines in the northern hemisphere.
Given the experimental nature of these vaccines it is not surprising that unexpected adverse events occur. Risk perspective can be understood by noting that thrombosis/thrombocytopenia complicating heparin therapy—an everyday event in clinical medicine—occurs 500 times more frequently than it does after COVID-19 vaccination.
The panic reaction, where major changes in vaccine policy are made on the basis of thrombosis occurring in one in 250,000 (with a mortality of one in 1,000,000) must be balanced against the risk of getting COVID-19. This is more complex in Australia and New Zealand where there is negligible COVID-19 in our community. In the northern hemisphere the maths is easier. The US and UK have respectively had 33.2 million and 4.5 million documented COVID-19 patients. Currently 20 per cent of blood donors in the US have anti-COVID-19 antibodies.
Using modelled data for deaths avoided by vaccination and deaths reported as adverse events (discussed below) in the USA, an approximate index can be calculated as a guide to vaccine use. For mRNA vaccines (Pfizer and Moderna) the ratio of deaths prevented over deaths reported as adverse events under fifty years is 4 to 5, and over fifty years is 35, giving strong support for vaccinating older subjects. Ratios for the same age bands with a DNA vector vaccine (Johnson & Johnson) were 2 and 25, again strongly supporting the value of vaccinating older subjects. These are at best indicative figures relevant to the USA with its high background numbers of recovered COVID-19 subjects, and current deaths at 200 to 600 per day (the lowest since late March 2020) and 40 per cent fully vaccinated. These statistics reinforce an imperative to continue vaccinating the more vulnerable as claims are made that the USA is approaching a degree of herd immunity, where immunity in a high proportion of the community resists the spread of infection to non-immune subjects, is attainable.
Circumstances could not be more different in Australia, where COVID-19 immunity from infection is essentially non-existent and we are a long way from any consideration of herd immunity.
Australia’s current level of community vaccination is about 10 per cent, and we present a population vulnerable to catastrophic COVID-19 infection resembling the horrors experienced in the northern hemisphere. As this article is written, another concerning community spread of virus with a fourth lockdown is occurring in Victoria, with associated economic and health issues on show, reminding us of our vulnerability. Vaccination will not prevent ongoing pockets of community infection but will support public health measures to limit their extent and give confidence to those making community decisions.
The other reason for community vaccination in Australia is that without significant community immunity, the relaxation of border controls would lead to a devastating and uncontrolled spread of infection, of the order experienced elsewhere.
Drugs used on a prophylactic and early treatment basis must be included in the strategic response to COVID-19 (discussed below).
If vaccination of at least 80 per cent of the community is accepted, as it should be, the question becomes, “Which vaccine?” The idea that influenza vaccination would be a model is, in my view, becoming likely: COVID-19 vaccines will prevent serious disease to a greater extent than acquired “infection”, with a shift towards mild disease and asymptomatic infection, but with ongoing and variable loss of protection against mutants. There will be less protection in the elderly. A limited duration of effect plus the appearance of vaccine-resistant mutants will mean annual booster shots matched to circulating variant virus will be required. Natural protection following COVID-19 disease is around 90 per cent at six to seven months, which means those with a history of infection do not need to be vaccinated (indeed, should not be vaccinated, as adverse events are more frequent for them).
Most countries have an official referral system for reporting adverse events following vaccination. In the US this is VAERS. Considerable controversy always surrounds such systems that can both under-estimate and over-estimate vaccine causation for reported events. VAERS has been criticised for having only 1 to 10 per cent of adverse events reported. Again the influenza model gives guidance, with the highest post-vaccine death rate at one in 1,000,000 reported for a batch of H1N1 vaccine in 1976, leading to this vaccine being removed from the market.
This contrasts with figures for mRNA vaccines recorded by VAERS at thirty to forty deaths per million for completed vaccinations, which is highly concerning. Adverse event reports are valuable only as indicative of a problem, with the weight of proof of a causative relationship depending on identifying a mechanism and analysis of epidemiological parameters.
The major cluster of deaths is in the first days after vaccination, due to a systemic inflammatory response, mainly in older subjects who appear to have had COVID-19 infection prior to vaccination. The cause of death is likely antibody and sensitised T cells, generated from previous infection or vaccination, reacting with high levels of the spike protein, encoded by the mRNA or the DNA vector vaccine, being expressed on cell surfaces, and circulating in blood, following injection of a genetic vaccine. This is consistent with severe adverse events reported more frequently with the second vaccine injection. Recent studies show spike protein persists in blood for at least two weeks after vaccination, with its production by cells throughout the body ensuring a systemic distribution of antigen. A possible second mechanism may be a direct toxic effect on small blood vessels, of the spike protein circulating in blood. This has been documented in laboratory studies and would account for the leakage of fluid from damaged capillaries seen in some of those with severe adverse events, following vaccination and also in COVID-19 disease.
Several epidemiological observations also support a causative relationship. First, similar high mortality rates of around thirty to forty per million are described in Europe, the UK and South Korea—all areas with high numbers of COVID-19 infections. Second, a Canadian epidemiologist, Jessica Rose, has completed a careful analysis of the VAERS data base, using the Bradfield Hill Criteria for Causality. She concluded that her analysis strongly supports a causative relationship. Third, the frequency of reported events short of death, but expected if vaccination was causative of death, was found to be commensurate: admissions to hospital of eighty-five per million vaccinations; emergency care 200 per million; and medical office visits 260 per million. Rose extended her analysis to the occurrence of spontaneous abortions, given reported concerns with respect to vaccination of pregnant women, and found a “time ordering” relationship suggestive of causation. Another group that requires further analysis is young children, given reports of cardiac involvement with myocarditis following vaccination.
Why are safe and effective drug treatments rejected?
The most difficult issue to understand in the COVID-19 saga has been the rejection by much of Western medicine of the value of cheap, safe and effective re-purposed therapies. This extraordinary situation and its driving factors of ideology and Big Pharma, have pervaded society from early in the pandemic. My 13-year-old grand-daughter says hydroxychloroquine (HCQ) is a “hoax drug”.
An updated summary of clinical studies for HCQ identifies 245 studies of 368,128 patients, with 64 per cent improvement in twenty-six early treatment trials. Some of these studies are short of perfect— which is to expected in the chaos and urgency of a pandemic. The scream of the armchair “experts”, none of whom seem to be caring for sick people, for Randomised Controlled Trials (RCT) should be (but strangely are not) accepting a significant 46 per cent improvement in six early treatment RCTs. Every study showed improvement. Thirteen studies showed 72 per cent lower mortality. Meta-analysis of thirty-four pre-exposure prophylaxis studies gave 28 per cent improvement (P < 0.001).
Ivermectin (IVM) has seen more recent interest because of the political connections of HCQ. Of thirty-seven studies, there was 81 per cent and 96 per cent lower mortality respectively for early treatment and prophylaxis, which included all of seventeen RCTs. All these results are statistically significant, and details are available on the public record.
Equally interesting results have been published for inhaled steroids and colchicine, both drugs with a long history in treatment of numerous diseases.
HCQ has little role in hospital (late) treatment, whereas IVM does appear to have a role in late treatment. Experienced clinicians stress the value of multi-drug therapy, especially adding a broad-spectrum antibiotic such as tetracycline, and zinc and vitamin D, for optimal impact.
Combining HCQ and IVM with zinc, vitamin D and tetracycline, Peter McCullough, of Baylor University in the US, treated 869 high-risk early-disease subjects over the age of fifty, finding 87 per cent and 75 per cent, respectively, in reductions to admission to hospital and death (P < 0.0001) compared with untreated controls. This is dramatic data, yet “experts” continue to insist on “more studies” for such therapy, while accepting the use of patented Remdesivir, from Big Pharma, at about $4000 a course, as useful therapy, following a single RCT showing the only benefit is four days less in hospital. These marginal results for Remdesivir could not be repeated in three subsequent RCTs.
Numerous regions in South America, Mexico and India (Goa) have introduced IVM or HCQ across the board for their residents, with impressive reductions in COVID-19.
To the question, “How could one expect these old drugs to have such a global effect against so many diseases?”, the answer is that all these drugs affect intracellular processes involved in handling macromolecules including microbes and autoantigens. They block assemblage of intact virus by different mechanisms, rather than having a specific “antiviral” effect of the type seen with base analogues. Combined with the capacity to buffer the inflammatory response, they have invaluable roles in treating a wide range of infections and chronic inflammatory diseases, COVID-19 included.
So where are we in mid-2021?
COVID-19 is a constantly moving challenge. We do not know all the answers, but a pathway to living with the virus can be identified, spelt out in a five-step program, listed above. There will be amazing discoveries before this pandemic is over—but that may not be for some time to come. In the meantime, we have to live with what we have. We should control local viral spread and move to open our national borders safely. Maintaining quality public health measures is a given. Then select an efficient and safe vaccine capable of modification to match relevant mutations.
Whichever vaccine is chosen, it will have limitations imposed in part by the biology of mucosal compartment infection and will have characteristics of the influenza vaccines. Current evidence suggests that it is unlikely any vaccine will stand out as being more efficacious than another. This includes the two Chinese inactivated virus vaccines with short-term protection at 73 per cent and 78 per cent in Phase 3 data just released.
There are high levels of serious adverse events for both mRNA and DNA vector vaccines that have attracted little attention. These reactions are probably caused by uncontrolled systemic antigen synthesis following vaccination, interacting with antibody from previous infections or immunisation. Deaths reported in the US from “systemic inflammation” within a day or two of vaccination at thirty to forty per million is unacceptable in the long term. It is thirty to forty times the death rate from thrombotic complications, which have been front-page news in recent times. These data are from countries with high background incidence of COVID-19 infections, unlike Australia. It is unlikely Australia will see these levels of post-vaccine death during the current first round of vaccination as the condition of immune priming does not exist. Second injections and future booster shots could create very different outcomes. Monitoring adverse events following second mRNA vaccine shots must be obsessive, with post-vaccination systemic reactions requiring hospitalisation an index of concern. Those recovered from COVID-19 do not need to be vaccinated and should not be given vaccine unless they are seronegative. Antibody screening should be put in place to assess changing community immune status, and to identify relative risk.
With respect to COVID-19, Australia is on a knife edge. Genetic vaccines are needed for the current Australian challenges of protecting the community from the ever-present threat of quarantine leak and out-of-control community infection, and to facilitate opening national borders. However, the risk of genetic vaccines must be understood and monitored. Mortality and morbidity data from the northern hemisphere signals the importance of care in future vaccine selection, and pressures from vested interests must be resisted.
Science and common sense strongly suggest that for the near future, three factors must be considered and acted upon.
First, alternative vaccines based on “classic” antigen formulation should be accessed and assessed as potentially safer options for the future. The good news is that Australia has acquired 51 million doses of the NovaVax “modern” antigen vaccine. This vaccine is a recombinant cloned spike protein, embedded in the surface of a nanoparticle, giving a clever formulation known as a virus-like-particle. In 15,000 subjects in the UK, it gave 89 per cent protection with no significant adverse events. This trial and another in South Africa gave good protection against two mutant strains that were less vulnerable to existing vaccines. The technology can rapidly be adapted to emerging mutants, which is important for long-term vaccine strategy. The point of difference for NovaVax is that there is no uncontrolled systemic synthesis and distribution of spike protein, avoiding life-threatening “systemic inflammatory disease”.
Recent publication of Phase 3 data from two Chinese trials, testing “classic” inactivated virus vaccines in 40,000 subjects, confirmed the efficacy of “antigen” vaccines, with no “systemic inflammatory” complications. As antigens are not negatively charged in the fashion of nucleic acids, thrombotic events are also unlikely. Of course, real-life experience can always surprise us, as seen with the genetic vaccines, although 100 years of experience with “classic” antigen vaccines with depot adjuvants reduces such concerns.
Second, local Australian control of vaccines makes much sense. Current thinking by government encouraging local manufacture of mRNA vaccines, is to say the least, concerning and premature. The efficacy/adverse event relationship of all vaccines, as well as technical issues, must first be resolved. For many years we have guaranteed supply with local production of an antigen-based vaccine (influenza) adapted to contemporary virus mutants. At this stage data and science favour antigen vaccines over genetic vaccines. Early evidence that genetic vaccines can re-model the immune apparatus, with hypersensitivity and autoimmune complications in the short term, together with localisation of spike protein in the brain, heart and other tissues, predicts possible long-term complications involving brain, heart and other tissues. Monitoring of both adverse events and virus genotype is central to long-term vaccine strategy.
Third, immediately establish safe and effective early treatment, and pre- and post-exposure prophylaxis, protocols to complement the vaccine program. These regimens, based on overwhelming science, should include HCQ and IVM. In the absence of sterilising immunity, there will always be a need for effective early therapy, and prophylaxis as back-up to vaccination, to protect individuals and reduce the community spread of virus. Such simple treatment saves lives and could be immediately in place.
Professor Clancy is a practising clinical immunologist with interests in autoimmune disease, immunisation and mucosal inflammatory disease. He was Foundation Professor of Pathology at the University of Newcastle, where he established the Newcastle Mucosal Immunology Group, identifying mechanisms of airways protection and the pathogenesis of mucosal disease, and discovered new methods of disease control