A Protective Layer for Humanity: Ultra-Broad Spectrum Open Source Vaccines for SARS-CoV-2 Variants and Future Epidemics:  - Phase 3 Trials and Additional R&D
 
VVV: Vaccines for Virus Variants
Vaccines of The People, by the People, and for the People

Quote from the Digital Citizen Community:
The big pharma vaccine development pipeline that takes out one or several variants at a time is a beautiful thing. But it should be combined with the complementary strategy of delivering public domain broad spectrum vaccines to the world. Whack-a-mole is good, but we also need a fence to keep the majority of the critters at bay.

Abstract

​This is a global social and scientific venture to create “ultra-broad spectrum” (UBS) vaccines to protect against multiple diseases at once, including future epidemics and pandemics, and SARS-CoV-2 variants of concern.  It leverages a cutting-edge mechanism called “trained innate immunity” (“Trained Innate Immunity, Epigenetics, and Covid-19,” https://www.nejm.org/doi/full/10.1056/NEJMcibr2011679, 2020).  The initial focus is on repurposing widely-available existing off patent/low-cost vaccines with evidence of broad-spectrum protection; ultimately one can create novel vaccines. Initial projects include a Phase 3 vaccine trial against COVID-19 in Brazil commencing in May 2021, and studies in South Africa.   Both are places where SARS-CoV-2 variants are dominant. Spreading globally, these variants have been shown to elude some new COVID-19 vaccines. Forging an alternate legal and economic model of vaccine development, some UBS vaccines could be made open source/open IP ab initio, and the “common property of all humankind,” available for non-exclusive production and broad use

1. Who is Involved

​A. OSPF Scientific Advisory Committee

1. Dr. Robert Gallo, MD.  Co-discoverer, HIV; renowned virologist; most widely cited scientist in the world for a decade; Founder, Institute for Human Virology, University of Maryland School of Medicine; Co-Founder, Global Virus Network, leading global network of virologists. (confirmed)
2. Dr. Tachi Yamada, MD.  Former Chair of Research & Development, GlaxoSmithKline; former President of Global Health, Bill and Melinda Gates Foundation, former head of R&D, Takeda Pharmaceuticals; Venture Partner, Frazier Healthcare. (confirmed)
3. Prof. Mihai Netea, MD, PhD.  Radboud Univ, The Netherlands.  Leading expert in trained innate immunity, PI of several clinical trials in vaccine repurposing. (confirmed)
4. Prof. Zelalem Temesgen, MD, Professor of Medicine, Mayo Clinic, Infectious Disease Specialist, Director, Mayo Clinic Center for Tuberculosis (confirmed)
5. Dr. Gurusingham Sittampalam, PhD, Senior Advisor to the Director, US National Institutes of Health, National Center for Advancing Translational Sciences (confirmed) 
6. Bernard Munos, MBA. Specialist in radical pharma innovation, 30 years at Eli Lilly, named one of 25 most influential people in biopharma globally, co-founder, OSPF. (confirmed). 
7. Dr. Stanley Plotkin, MD, Consultant and Emeritus Professor, Univ. of Pennsylvania. Helped invent rubella vaccine. Author of leading textbook on vaccines. Advisor on vaccines to Sanofi and others. Co-founder, Center for Epidemic Preparedness Innovation.  (in our network, to be approached)
8. Prof. Megan Murray, MD, DPH, Professor, Harvard Medical School and Harvard School of Public Health (in our network, to be approached)
9. Dr. Jerome Kim, MD, Director General, International Vaccine Initiative, Seoul, Korea (in our network, to be approached)
10. Dr. Ole Oleson, PhD, CEO, European Vaccine Initiative  (in our network, to be approached)
11. Dr. Peter Small, MD, University of Washington (in our network, to be approached)

B.  Principal Investigators

1. Prof. Mihai Netea, MD, PhD.  Radboud Univ, The Netherlands.  Leading expert in trained innate immunity. https://www.nejm.org/doi/full/10.1056/NEJMcibr2011679; PI of several BCG trials.  https://www.cell.com/cell/fulltext/S0092-8674(20)31139-9; https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31025-4/fulltext; Co-PI, Brazil Trial (confirmed)
2. Prof. Sergio Henrique Nascente Costa (Goias Faculty, Goiania, Brazil):  Co-PI.  (confirmed)
3. Prof. Michael Avidan, Washington Univ. School of Medicine, St Louis, USA. Global PI for CROWN MMR COVID-19 trial, https://clinicaltrials.gov/ct2/show/NCT04333732 and five CROWN colleagues across South Africa - PIs, South Africa Trial (confirmed)
4. Prof. Shabir Madhi, PI, Professor of Vaccinology, University of the Witswatersrand, co-founder and co-Director of the African Leadership Initiative for Vaccinology Expertise (ALIVE).  PI, South Africa Trial  (in principle yes)

C.  Sponsors and Partners

1. Partner:  Global Virus Network, leading global network of virologists, with 66 institutional members in 34 countries. www.gvn.org
2. Sponsor:  Open Source Pharma Foundation, a Southern-based global nonprofit. dedicated to medicine for all, and to creating a global open source pharma ecosystem, with a focus on repurposing for respiratory pandemics. www.ospfound.org​

NDTV: Can Open Source Vaccines Become a Reality for India?

Watch Jaykumar Menon, co-founder of Open Source Pharma Foundation and human rights lawyer, who talks to NDTV's Vishnu Som about a platform where scientists and researchers can freely access technological tools for researching diseases, share their discoveries and start new investigations into potential drugs. If the platform succeeds, it will allow drugs to succeed on their merit and need, rather than their ability to be profitable.

watch video

2. Executive Summary

​A. Introduction
​
SARS-CoV-2 virus variants of concern (VOCs) are a growing problem.  They are more infectious than the original strain, and their prevalence is increasing rapidly. Worrisomely, some COVID-19 vaccines have been shown to be ineffective against VOCs. Finally, evolution favors the variants.

We must guard against a scenario where SARS-CoV-2 variants elude vaccines and ravage humanity.  The downside risk is simply too high.  It would be prudent, cost-effective, and even imperative, for the world to try to prepare a slate of universally accessible broad-spectrum vaccines to protect against variants.  They could also prevent other diseases, and future epi- and pandemics, potentially even before they start.

To solve the problem, we can draw from a new paradigm in immunology. If the data from the proposed project bears out, we can create what has long been considered a holy grail, and a moonshot, or even beyond that – an “ultra-broad spectrum” (UBS) vaccine, which prevents many diseases at once, with the added advantage of being nearly universally accessible.
​
B. Two Paradigms in Immunology

The classical approach in immunology focuses on what is known as the adaptive immune system.  This approach leads to the design of very narrowly-targeted vaccines that are highly effective against a very specific and original strain of single bacteria or virus, but that are perhaps not effective against its inevitable variants, let alone other diseases.  This approach has been deployed with stunning speed for COVID-19, with massive credit owed to all involved, although huge issues of equitable access and hesitancy remain. 

However, we are still playing a global game of catch-up:  for every new epidemic or pandemic, a new vaccine will take roughly a year or more to develop, and additional years to distribute.  And the variants bedevil. Further, other potentially preventable diseases go unchecked. In the interim, billions of people suffer, trillions of dollars are lost, and societies are locked down.  The gap is too long and costly.

The emerging paradigm favors breadth.  It focuses on what is called the innate immune system, that which defends across pathogens, and prevents many diseases at once.  This cutting-edge science could, again if the data bears out, potentially enable a new and singular class of vaccines.  Every vaccine in the world today - whether live-attenuated, inactivated, viral vector, mRNA, or other – is designed to target the adaptive immune system. This new class of vaccine would, by contrast, would target the innate immune system, which enables provide broad spectrum protection.

C. Innate Immunity and Ultra-Broad Spectrum Vaccines

Is a UBS vaccine within reach?  Our considered answer is yes.  The latest peer-reviewed basic science research, published in authoritative journals such as the New England Journal of Medicine and Cell, elucidates the mechanism. Coupled with decades of clinical trial evidence, it tells us that a UBS vaccine is indeed feasible, and further yet, and perhaps startlingly, already well-established, at least with respect to several non-COVID-19 diseases. 

But first, a prefatory note. While the science and data are sound, the innate immunity-based approach is admittedly novel, so much so that it may require a sufficiently open scientific and industrial temperament to receive it.  There may be something here that smacks of Thomas Kuhn’s discussion of changing scientific paradigms.  But of course, novelty, if founded, is the very basis of scientific advance. And although the analogy is imperfect, it may be worth remembering that synthetic mRNA approaches, now central in the vaccine landscape, were dismissed and unfunded for decades.

D. Innate Immunity and Ultra Broad Spectrum Protection – Mechanism

So, as to the science:  how exactly does this work? How can one vaccine prevent many diseases?  Certain existing vaccines (the phenomenon is most well characterized to date in live attenuated vaccines, where a living weakened cell is injected into the body) activate and tune our overall innate immune system - a sort of protective moat that successfully handles the vast majority of infections during the course of in our lives – and cause it to bloom.  This provides us with a fairly pathogen-agnostic, “off-target,” broad spectrum protection against many diseases at once.  This sophisticated, powerful, and only recently-understood mechanism, systemic and almost symphonic in its operation, in contrast to the lock-and-key model of the classical approach, is known as "trained innate immunity,” as published recently in the New England Journal of Medicine, Science, and Cell, and described further below.[6]  In essence, some existing vaccines activate both the innate and adaptive immune systems, and may owe their broad effectiveness to a synergistic effect.  In sum, the body is a complex system, and by making sure to train and precisely stimulate our overall, natural, innate immune system - our first, fastest, most deeply evolutionarily rooted, broadest, most frequently used, and most frequently successful line of protection – a vaccine can prevent many diseases at once.

E. Innate Immunity and Ultra Broad Spectrum Protection - Evidence

It has been known for nearly 100 years a live attenuated vaccine can prevent many diseases at once, reducing “all-cause” mortality.  Decades of published clinical trials have borne this out.  A recent pre-COVID clinical trial amongst the elderly of one such vaccine found a remarkable 79% reduction in all respiratory diseases of probable viral origin,  which are a major cause of hospitalizations among the elderly  This would seem to merit large scale deployment among the elderly, or at the least additional large-scale studies. Merck even uses one of these vaccines, the BCG tuberculosis vaccine, as an approved therapy for bladder cancer, indicative of its broader effects. 

With regard to COVID-19 in particular, the jury is out.  There is some evidence of efficacy of certain existing vaccines from other diseases, via ecological studies, structural homologies, mechanism elucidation, and clinical reports, with results from small clinical trials emerging over the next year.

Concerning efficacy, while a UBS vaccine may not provide the same ninety plus percent effectiveness against a single pathogen as a narrowly-targeted vaccine, a UBS vaccine has myriad other advantages.  It can a) still potentially be quite effective against a given pathogen, b) be used on a stop-gap basis, while a narrowly-targeted vaccine is being developed and distributed, c) be used in combination, to increase duration or efficacy, d) protect against a broader range of variants, pathogens, and diseases, and e) perhaps have longer duration, e.g. they may protect two years or more.

F. Brief Time Till Impact

Unusually, the basic science here is poised for rapid health impact. Typically, it takes several decades to move from basic science discovery to broad societal impact.  Here, of course, we should try to create over the long term a new generation of novel vaccines that leverage innate immunity and provide ultra-broad spectrum protection.  But to attain impact even more quickly, and to fight this pandemic, we can turn to existing vaccines from other diseases. Broad spectrum cross-disease protection via trained innate immunity is already known to be provided by a few existing, fully approved, off patent or low-cost vaccines that happen to also have widespread manufacture, distribution, and acceptance, with decades of safe use, and an existing reach of billions, with huge stockpiles, and which are ready for phase 3 clinical trials, cost as little as pennies a dose, and could reach much of humanity rapidly.  These include the live attenuated vaccines of BCG, OPV, and MMR, as well as possibly yellow fever, and possibly other vaccines such as influenza and zoster.

Research and development in this promising area of trained innate immunity, despite its high health potential, is under-resourced. This is partly because it is a new and emerging avenue in immunology. And it is partly because of simple market failure, as the repurposing off patent or low price vaccines, a logical point of departure, provides insufficient ROI for large industry (which, apart from the government-funded COVID-19 efforts, has relatively limited investment in vaccines in the first place, given the short revenue streams).

G. Short Term Program

We propose here a program of basic science, product development, and eco-system creation.  The program will be pathbreaking, and if the evidence generated bears out, world-changing. It will at the least accomplish a few large things:  build the emerging paradigm of innate immunity; create a new field – that of vaccine repurposing; and explore a new class and paradigm of vaccines, focused on the innate immune system. 

In the immediate term, we would begin with:
a) immunological studies.  Using blood samples, but not necessarily part of clinical trials, these would explore the use of repurposed vaccines against SARS-CoV-2 variants globally. The studies would also examine the pivotal question of whether various putative broad spectrum vaccines, given in combination with various tightly-targeted vaccines, enhance efficacy or duration of protection.
b) phase 3 clinical trials.  These would explore the efficacy of existing low-cost vaccines from other diseases that have already shown strong evidence of eliciting trained innate immunity and providing broad spectrum protection.  We will conduct phase 3 trials in Brazil and South Africa, with a focus on MMR, influenza, and possibly others, exploring efficacy against the SARS-CoV-2 variants there. The variants are both widely prevalent and are known to escape the narrow vaccines.
c) retrospective and observational studies.  These would explore efficacy of the existing vaccines with broad spectrum potential, using extant massive clinical data sets.

H.  Long Term Vision

The long-term project is to explore building an armamentarium for humanity, a sort of public-spirited and public-supported Manhattan Project. The ethical and scientific vision: a global protective layer, protecting all humans against pathogens known and unknown, comprised of broad-spectrum public domain vaccines. nonexclusively produced, and, to draw from the phrase in international law, the “property of all humankind.”  Vaccines by humanity and for humanity, to cost-effectively and rapidly prevent a wide range disease amongst all humans, across ages, in countries rich and poor.  Imagine a Martian looking at the Earth, observing humanity under existential threat from a germ. Would they not expect the solution to be open source – developed rapidly and iteratively, bv all working together, made by all, available to all?  And even more so if it were funded from the public trough?

In more concrete terms, the long-term project involves conducting further basic science, and product development, and, as needed, work in adoption, partnerships, and awareness, seeking to create ultra-broad spectrum vaccines that are universally accessible (by virtue of being open IP or low cost, with large extant stockpiles and manufacturing). This might involve a large, global, adaptive clinical trial. One could even envision developing a novel, single, unitary, widely accessible vaccine that combines the broad spectrum aspects of multiple vaccines into one, a single vaccine that could protect against multiple classes of pathogens - coronaviruses, hantaviruses, and other infectious agents- including, wondrously, against pathogens as yet unknown and not yet emerged.
One might take inspiration from the Salk polio vaccine, which was as nearly important in its time as COVID-19 vaccines are today.  The Salk vaccine was crowdfunded, patent free, and backed by a pharma R&D nonprofit founded and run by New York lawyers, in a collaboration between Franklin Delano Roosevelt and Jonas Salk.

I. Practical Importance and Conclusion

If the effort is successful, how could these ultra-broad spectrum innate immunity-boosting vaccines be deployed?  In five principal ways:

1. Other Diseases. We already have strong clinical trial evidence that certain vaccines protect off-target against non COVID-19 diseases—see the pre COVID ACTIVATE trial among the elderly in Greece, in which BCG vaccination reduced all respiratory infections of non-viral origin by 79%. Those are ready for deployment or at least further study.
2. Bridge Vaccination.  In case of an epidemic or pandemic, such vaccines be rapidly deployed to providing partial protection, particularly to the vulnerable, to bridge the period until specific vaccines are developed.  Here the creation of immunity within one hour (via innate immunity) rather than in two or more weeks (via adaptive immunity) becomes very important.
3. Pre-Pandemic.  With, for example, booster shots of safe UBS vaccines every five years, or possibly even less frequently, pandemics could be curtailed or prevented from arising at all.
4. In Combination.  Since the mechanisms are complementary, giving combinations of UBS and narrow vaccines might provide greater duration or efficacy than either type alone.
5. One Vaccine to Rule them All.  In the long term, in addition to repurposing existing vaccines that elicit trained innate immunity, an important aim would be to design novel UBS vaccines that combine classical adaptive immune memory and trained immunity, to enhance even more strongly the immune response and to provide an improved broad protection.

 
Given the toll on humanity over the past year, the trillions in economic loss, or even the billions spent on vaccines to date, all of which is still mounting, this is a potentially high impact, high speed, orders-of-magnitude-less-R&D-cost element to add to our preventive portfolio. If we can complete well-founded phase 3 vaccine trials, coupled with widespread distribution, global accessibility, and broad acceptance, with variant protection potential, for a few million dollars, that is a worthwhile investment of trifling proportions.

And to put it bluntly, the cost of inaction is clear.  For the next epidemic or pandemic, and to curb SARS-CoV-2 variants, and to prevent other diseases, we need broad spectrum vaccines. Otherwise, at each outbreak, we have may mass death and shutdowns for a year or more.  Let us not repeat the experience of COVID-19.

VACCINUUM - Read full project