Fig. 1. The four pillars of pandemic response to COVID-19. The four pillars of pandemic response to COVID-19 are:
1) contagion control or efforts to reduce spread of SARS-CoV-2,
2) early ambulatory or home treatment of COVID-19 syndrome to reduce hospitalization and death,
3) hospitalization as a safety net to prevent death in cases that require respiratory support or other invasive therapies,
4) natural and vaccination mediated immunity that converge to provide herd immunity and ultimate cessation of the viral pandemic.

Robert Clancy explains in his Quadrant article  COVID-19: A realistic approach to community management The author is Emeritus Professor of Pathology at the University of Newcastle Medical School. He is a member of the Australian Academy of Science’s COVID-19 Expert Database.   Excerpts in italics with my bolds.

Historically pandemics generate suspicion, speculation and emotion, before logic and empiric decisions determine optimal management. The current Covid19 pandemic is no exception. Twelve months on, there is an emerging consensus supporting an integration of a four-pillar plan: public health strategies; vaccination; early pre-hospital treatment; and hospital treatment. This position replaces an early confusion, with supporting data appearing on a near daily basis.

Public Health strategies are well understood and highly effective, forming the bedrock for disease control, while hospital management is a work in progress, but with progressive improvement in outcomes. Typical data for high risk subjects (>50 years with 1 or more co-morbidities) in the USA is currently 18-20% hospitalisation, with mortality around 1%. Less attention has been given to ongoing symptoms, with about 80% of hospitalised patients having profound fatigue and/or breathlessness 3-4 months after discharge. Many are unable to return to full time work 6 months after infection control.

The area of intense disagreement is community management combining prevention by vaccine and reduction of hospital admission, using pre-hospital treatment.

There is a global expectation that vaccines will dramatically change the current face of Covid19 while there is broad based denial that any of the available (unpatented) drugs beneficially alter the natural history of infection. Expectation of a vaccine nirvana alongside therapeutic nihilism are both incorrect, although each is promoted with a vigour rooted in socio-political conviction (& supported by the Pharma industry).

The conclusion based on logic and data, is that vaccines and early treatment strategies are both necessary for optimal disease control. As a result, a community plan has been formulated, aimed at keeping patients out of hospital. Experienced physicians have developed protocols based on evidence, with sequenced multi-drug regimens that support >80% reductions in admissions to hospital and death.

Implementation of this approach would effectively end the US, UK, Canada, and EU hospitalisation crises.

The objective of this brief review is to provide argument in support of these conclusions, based on an untangling of the pathobiology of Covid19 over the last 12 months; review of the available data on the three vaccines used in the western world; and current data supporting significant benefit of pre-hospital drug treatment.

The Vaccine

The idea that a vaccine would induce sterilising immunity and therefore prevent community spread by creating herd immunity, has become the dominant political and medical story. Political, economic and social planning has been based on a sense of certainty that this will happen. This was never a likely outcome, as such success was asking more of the immune apparatus responsible for containment of a respiratory virus, than had been observed. The first principal of vaccinology has always been that a vaccine is unlikely to give better protection than does the disease itself. First cousin Corona viruses cause recurrent airways infections over many years, manifest clinically as “common colds”. Recurrent Covid19 infections have been documented during the first year of the pandemic. Mucosal immunological memory for corona viruses is predictably poor.

The objective of any Covid19 vaccine is to limit virus replication within the mucosal compartment of the airways. This requires specific activation of the mucosal immune system, which differs from systemic immunity, geared to protect the internal spaces of the body. Blood antibody levels characterise the systemic immune response. These antibodies are very effective at neutralising virus that passes through the blood stream in its normal course of infection, such as the measles or mumps virus. These vaccines readily induce sterilising immunity.

The relevance of this immune machinery to Covid19 vaccines can be summarised:

•  the systemic and mucosal immune compartments communicate poorly, with minimal mixing. Some mixing occurs in regions such as the nasal cavity and the alveolar space as demonstrated by injected pneumococcal vaccines where IgG antibody from blood can inhibit pneumocooci in the nose and the gas exchange apparatus of the lungs and thus protect from ear infections and pneumonia. This may explain the high level of “PCR-ve Covid19 infections” (that is, apparent clinical infection by Covid19 virus, but with a negative laboratory test in the mRNA trials, as discussed below. 
• mucosal immune responses to the virus are transient.
• immune senescence at a mucosal level is marked.

Three vaccines have been released in the US and UK after limited observation and review due to the dramatic circumstances of the pandemic. . . The outcome of these reviews suggest that little difference exists between the three vaccines.  To summarise current position with vaccines;

• Little protection against infection occurs, although protection against symptomatic disease is significant, but is likely to be far less than 90%. It remains to be demonstrated whether this translates into protection against admission to hospital, & mortality since this was not the case in 2 months of follow-up with the mRNA vaccines. The duration of protection and level of protection in high risk individuals over time, need to be monitored. The likely outcome is that vaccines push the disease profile towards asymptomatic infection, rather than induce any discrete sterilising immune state. It is unhelpful and risky to attempt to choose between available vaccines until far more data becomes available.
• Re-infection in vaccinated subjects appears to occur at a similar rate as it does for community non-vaccinated controls.
• There is no realistic chance of herd immunity, given the high rate of asymptomatic infections in vaccinated individuals. This becomes more probable should the current intention of about 30% of the population (US figures) to not be vaccinated irrespective of advice given, be accurate. In Australia, every encouragement should support over 90% vaccination, with whatever of the available vaccines are available: dissention and argument over “false news” undermines this endeavour. In other words, though immunity with Covid19 vaccination appears to be neither complete nor durable, any chance of approaching “herd immunity” depends on a near 100% vaccination rate. Time will give answers to the critical questions, and vaccines still in trials, may be a better choice in the longer run. None of the “clever” delivery systems have yet proved to be an advantage over traditional (or 21st century variations) adjuvenated split vaccines (other than for those who own the patent).
• It can be predicted that endemic spread of the virus throughout the population will occur. The observations in the UK trial of high levels of asymptomatic infection, and “Diagnostic Test Negative” infections in the Pfizer study, focus attention on confirming the dynamics of asymptomatic infection post vaccination, and the degree of transmission in the community, from that source. Data on these critical issues is limited.
• There is a potential danger that as vaccination levels increase, but remain short of comprehensive cover, virus could spread with “hotspots” difficult to identify. Such spread could promote the emergence of resistant strains.The worst scenario would be an increase in mortality due to spread from unrecognised vaccinated subjects with asymptomatic infection, to those without vaccination protection. On this, current data is scanty, indicating about 20% of Covid19 infections are asymptomatic, but that the infectivity of these, is reduced, perhaps 3-4 fold. Similar data in the post-vaccine world will be of central importance.

Early Drug Treatment

It could be summarised that in a “Post Truth World’, those with Covid19 disease are denied safe, effective treatment which if given early can reduce admission to hospital and death. The main purpose of the comments to follow, is to show that the data have moved on, and that science-based decisions can and must be made if lives are to be saved. Two drugs are effective: hydroxychloroquine (HCQ), and ivermectin (IVM) with most effective trials including nutraceutical, zinc and intracellular antibiotics. These antivirals have been available as antimicrobial drugs for many years. Their antiviral activity is due to intracellular processes that inhibit virus assemblage – HCQ reduces acidity within cytoplasmic vesicles, and IVM blocks communication between the cytoplasm and the nucleus, while both have many sites of action that impair the inflammatory response.

The basic principal in treating viral infections is to treat early. This is well established for all virus therapy including acyclovir treatment for shingles, herpes simplex infections, and neuraminidase inhibitors in influenza. The same principal applies to treatment of Covid19. Treatment during the first “virus dominant” phase is directed at reducing the viral load within the mucosal compartment, while in the second phase treatment aims at inhibition of the damaging inflammatory response. Patients with significant second phase disease are usually in hospital, and treated with organ support, anticoagulation and anti-inflammatory drugs.

The data base supporting the value of early treatment of Covid19 disease is so strong, that it is hard to understand the current philosophy of “wait until you are sick enough, then go to hospital” (The question I put to naysayers is “would you give or not give HCQ or IVM to your grandparent with early Covid19 disease in an Australian aged care facility?”). Suggested reasons for unscientific denial include: ideological unmovable mind sets; a rapidly evolving pandemic where new data appears on a daily basis making it hard to keep up with the data flow; failure to understand the value of non RCT data sets which from a scientific and ethical viewpoint are appropriate to the circumstances of a pandemic; and a total focus on an anticipated Covid-free world following the release of vaccines.

The RCT mantra selectively used against HCQ and IVM is cynical, given the experience with Remdesivir. This antiviral agent has been tried in the treatment of Covid19 and was shown in a RCT to reduce time in hospital by 4 days, with no reduction in mortality. On this scanty evidence it was rushed through the regulatory process. Although three additional RCTs failed to confirm this slight benefit, it continues to be used at around A$4,000 a course, with many significant side effects.

Review of clinical studies in early (pre-hospital) disease as at end of November 2020 illustrate the data:

• All 27 trials of HCQ showed protection (OR 0.37 (0.29-0.47)). 10 of these were RCT (OR 0.71 (0.54-0.95)) (the Odds Ratio , or OR of , say, 0.37, means “63% protection”, and 0.71 would be “29% protection”). The figures in ( ) are the 95% confidence levels: if <1.0, this is equivalent to {at least } a P value <0.05) (P value refers to probability of result being by chance. A value of 0.05 means a 1 in 20 chance that it is “by chance”, with that level taken as reflecting a significant observation).
• 26 of 32 prophylaxis studies using HCQ showed protection (OR for 5 post exposure studies: 0.61 (0.4-0.74))
• IVM in 8 studies, half of which were RCT, showed protection in early treatment studies (OR 0.28(0.13-0.59) P=0.004)

As this clinical data continues to accumulate, regions around the world are adopting therapy with HCQ or IVM with dramatic results, when compared to adjoining areas that have not adopted this therapy. This has been marked in regions in Brazil.

The incidence and mortality of Covid19 in the US and Europe is of crushing proportions with no end in sight. . . Planning on the basis that all this will change following introduction of vaccines, needs reassessment, as early review of trial data, while showing short term protection from significant symptomatic disease, must be tempered by evidence that infection is little reduced when asymptomatic and “PCR-ve Covid19” (a negative test for virus on a nasal swab) cases are counted. . . Uncertainties regarding the capacity of current vaccines to attain herd immunity due to continued asymptomatic infection, dictate that additional measures to reduce the impact of the pandemic must be put in place.

Two drugs used early in disease reduce admission into hospital and death, including in those considered high-risk subjects, and they go a significant way to filling this need: HCQ and IVM. Both can be used as prophylactic or therapeutic medications. From uncertain beginnings, an impressive data base has more recently accumulated, that strongly supports the use of HCQ and/or IVM. Their use in concert with vaccines can no longer be denied; indeed this is the only science-based option.

Background from previous post Why Pandemic Responses Fail

As reported in the journal Reviews in Cardiovascular Medicine, Top US medics recommend ‘sequenced multidrug therapy’ including HCQ & Ivermectin, for early high-risk COVID-19 infections (source Palmer Foundation).  Bureaucratic public health officials obsessed with top-down, high-tech solutions have failed to provide citizens with the most important pillar: advice and the means to treat themselves and take charge of their own health care.  Excerpts in italics with my bolds.

The pandemic of SARS-CoV-2 (COVID-19) is advancing unabated across the world with each country and region developing distinct epidemiologic patterns in terms of frequency, hospitalization, and death. There are four pillars to an effective pandemic response:
1) contagion control,
2) early treatment,
3) hospitalization, and
4) vaccination to assist with herd immunity (Fig. 1).

Additionally, when feasible, prophylaxis could be viewed as an additional pillar since it works to reduce the spread as well as the incidence of acute illness.

Many countries have operationalized all four pillars including the second pillar of early home-based treatment with distributed medication kits of generic medications and supplements as shown in Table 1.

In the US, Canada, United Kingdom, Western European Union, Australia, and some South American Countries there have been three major areas of focus for pandemic response:
1) containment of the spread of infection (masking, social distancing, etc.,
2) late hospitalization and delayed treatments (remdesivir, convalescent plasma, antiviral antibodies), and
3) vaccine development (Bhimraj et al., 2020; COVID-19 Treatment Guidelines, 2020).

Thus the missing pillar of pandemic response is early home-based treatment (as seen in Fig. 1).

The current three-pronged approach has missed the predominant opportunity to reduce hospitalization and death given the practice of directing patients to self-isolation at home. Early sequential multidrug therapy (SMDT) is the only currently available method by which hospitalizations and possibly death could be reduced in the short term (McCullough et al., 2020a).

Innovative SMDT regimens forCOVID-19 utilize principles learned from hospitalized patients as well as data from treated ambulatory patients.

For the ambulatory patient with recognized signs and symptoms of COVID-19 on the first day (Fig. 2), often with nasal real-time reverse transcription or oral antigen testing not yet performed, the following three therapeutic principles apply (Centers for Disease Control and Prevention, 2020) :

1) combination anti-infective therapy to attenuate viral replication,
2) corticosteroids to modulate cytokine storm, and
4) antiplatelet agent/antithrombotic therapy to prevent and manage micro- or overt vascular thrombosis.

For patients with cardinal features of the syndrome (fever, viral malaise, nasal congestion, loss of taste and smell, dry cough, etc) with pending or suspected false negative testing, therapy is the same as those with confirmed COVID-19.

Fig. 3. Sequential multidrug treatment algorithm for ambulatory acute COVID-19 like and confirmed COVID-19 illness in patients in self-quarantine. Yr = year, BMI = body mass index, Dz = disease, DM = diabetes mellitus, CVD = cardiovascular disease, chronic kidney disease, HCQ = hydroxychloroquine, IVM = ivermectin, Mgt = management, Ox = oximetry, reproduced with permission from reference.

Summary

The SARS-CoV-2 outbreak is a once in a hundred-year pandemic that has not been addressed by rapid establishment of infrastructure amenable to support the conduct of large, randomized trials in outpatients in the community setting.

The early flu-like stage of viral replication provides a therapeutic window of tremendous opportunity to potentially reduce the risk of more severe sequelae in high risk patients. Precious time is squandered with a “wait and see” approach in which there is no anti-viral treatment as the condition worsens, possibly resulting in unnecessary hospitalisation, morbidity, and death.

Once infected, the only means of preventing a hospitalization in a high-risk patient is to apply treatment before arrival of symptoms that prompt paramedic calls or emergency room visits. Given the current failure of government support for randomized clinical trials evaluating widely available, generic, inexpensive therapeutics, and the lack of instructive out-patient treatment guidelines (U.S., Canada, U.K., Western EU, Australia, some South American Countries), clinicians must act according to clinical judgement and in shared decision making with fully informed patients.

Early SMDT developed empirically based upon pathophysiology and evidence from randomized data and the treated natural history of COVID-19 has demonstrated safety and efficacy.

In newly diagnosed, high-risk, symptomatic patients with COVID-19, SMDT has a reasonable chance of therapeutic gain with an acceptable benefit-to-risk profile.

Until the pandemic closes with population-level herd immunity potentially augmented with vaccination, early ambulatory SMDT should be a standard practice in high risk and severely symptomatic acute COVID-19 patients beginning at the onset of illness.

Authors:

Peter A. McCullough, Paul E. Alexander, Robin Armstrong, Cristian Arvinte, Alan F. Bain, Richard P. Bartlett, Robert L. Berkowitz, Andrew C. Berry, Thomas J. Borody, Joseph H. Brewer, Adam M. Brufsky, Teryn Clarke, Roland Derwand, Alieta Eck, John Eck, Richard A. Eisner, George C. Fareed, Angelina Farella, Silvia N. S. Fonseca, Charles E. Geyer Jr., Russell S. Gonnering, Karladine E. Graves, Kenneth B. V. Gross, Sabine Hazan, Kristin S. Held, H. Thomas Hight, Stella Immanuel, Michael M. Jacobs, Joseph A. Ladapo, Lionel H. Lee, John Littell, Ivette Lozano, Harpal S. Mangat, Ben Marble, John E. McKinnon, Lee D. Merritt, Jane M. Orient, Ramin Oskoui, Donald C. Pompan, Brian C. Procter, Chad Prodromos, Juliana Cepelowicz Rajter, Jean-Jacques Rajter, C. Venkata S. Ram, Salete S. Rios , Harvey A. Risch, Michael J. A. Robb, Molly Rutherford, Martin Scholz, Marilyn M. Singleton, James A. Tumlin, Brian M. Tyson, Richard G. Urso, Kelly Victory, Elizabeth Lee Vliet, Craig M. Wax, Alexandre G. Wolkoff, Vicki Wooll, Vladimir Zelenko. Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19). Reviews in Cardiovascular Medicine, 2020, 21(4): 517-530.