Healthier Uses For The $5 Billion NextGen Covid-19 Funds

Paraphrasing a line miscredited to Einstein: “Insanity is repeating the same mistakes and expecting different results.” With the just announced White House $5 Billion Covid-19 NextGen Project for vaccine research and development, it seems that our pandemic response lessons have gone unheeded. To be specific, why has research and development of a Real-Time Diagnostics Plan and Host Defense Therapies remained unfunded?

I must begin by recognizing a fundamental truth, for more than 200-years, vaccines have saved more lives than all other therapeutics combined. However, development of many effective vaccines for protection from modern day infections has, so far, yielded disappointing results.

In 1987, research started on development of HIV vaccines. To date, no HIV vaccine exists. Clinical trials of candidates remain challenging. And when you look at seasonal influenza vaccines, because they are based on “best guess” strain identification, demonstrate effectiveness of no more than 60%; some years, effectiveness plunges to as low as 10%. The need for a universal pan-influenza vaccine has long been recognized though dozens of approaches have been heralded over a span of 40 years, only a handful of candidates have advanced to late stage clinical testing… and none have yet succeeded.

A Covid-19 Pandemic Still Exists

From February to April 11, there have been 120,820 new weekly Covid-19 infections, 1,773 new weekly deaths, and 1,807 new daily hospitalizations reported. (Be mindful that there is no national strategy for Covid-19 reporting so the actual numbers are higher.) There is also no reason to believe that new vaccines will prove to be any more effective.

Given these grim realities, where would the $5 billion research and development funds be the most effective? As I will explain below in developing a comprehensive, real-time diagnostic plan and of equal importance, in focusing on host defense therapies. The benefit of equal importance would also be that these technologies would not be limited in use to just the coronavirus but could change much of how we practice medicine globally.

The problem(s) with the NextGen Goals

Covid Vaccine Limitations

Covid-19 vaccines were developed to perform by preventing the virus from infecting thereby holding it in check. The problem is, while the vaccine is specific in its mode of action attaching to a specific viral structure, the virus mutates and changes that vulnerable point to evade vaccine attachment. When it cannot attach to the virus, the vaccine becomes less effective at preventing infection and, instead must rely on other, yet undefined immunity to protect against death.

Despite this fact, there will still be proponents of the vaccine and booster strategy. However, the public has become less confident regarding vaccination recommendations. Given that just over 50% of Americans get a yearly flu vaccine, it is unlikely that that number will be larger for a new Covid-19 vaccine or vaccine booster. The only exception to this prediction would be the development of a pan-coronavirus vaccine administered as a one-and-done treatment. And as aforementioned, though theoretically possible, generations of research have failed to yield the desired result.

Monoclonal and Polyclonal Antibody Treatment Limitations

These therapeutics are especially important for those with compromised immune systems but cannot yield broad Covid-19 protection for the community at large. The reason is that they are too specific and are destined to attack a specific viral variant. Viruses survive by mutating to evade host defenses and therapeutics. A simple mutation can make antibody treatments ineffective.

Why not just keep developing antibody treatments against each new variant as they arise? Unfortunately, it takes too much time to develop, manufacture, distribute, and administer a new antibody treatment. By the time a new treatment is accessible against the current dominant strain, the virus has had time to mutate creating a new dominant strain making treatment against the former strain ineffective. Because of this cycle of decreased effectiveness, the FDA pulled its initial EUA authorization for multiple monoclonal therapies. There is tepid support for polyclonal antibody treatments however they are most effective when given before a patient becomes clinically ill.

Another challenge resulting from the use of antibody treatments is the development of Antibody-Dependent Enhancement (ADE). ADE occurs when the antibodies generated during an immune response (or injected through antibody therapy) recognize and bind to a pathogen but are unable to prevent infection. Instead, these antibodies function as “Trojan horses” allowing the pathogen to get into cells and to produce an unhealthy immune response leading to rampant inflammation.

A rarely discussed challenge resulting from antibody therapy is the development of immune system imprinting. Immune imprinting is a phenomenon whereby initial exposure to one virus strain effectively primes B cell memory and limits the development of memory B cells and neutralizing antibodies against new variant strains of the virus. If a patient’s immune system has been imprinted by a previous Covid-19 infection, a subsequent Covid-19 infection from a new variant will stimulate the immune system to produce antibodies to the older variant rather than the new one resulting in unrestrained infection.

What Is the Answer for the $5 Billion in COVID Funds?

A Host Defense Approach

To understand the need for improved host-defense therapies, one needs a basic knowledge of the body’s immune complement system whose disruption results in severe illness.

The complement system has three main components, each with a specific mode of action. The three limbs or pathways of the complement system are the classical, lectin and alternative pathways.

The classical pathway of complement is a key component of the adaptive or learned immune response and is activated by antibodies bound to foreign substances. It is critical to the body’s ability to fight infection.

The lectin pathway of complement plays a central role in the body’s innate immune response. The lectin pathway is activated by patterns of molecules on pathogens and on damaged cells within the body.

The alternative pathway is an amplification loop always running in the background of the complement system, and its activity is increased with activation of the classical and/or lectin pathways, enhancing the actions of those two pathways.

The complement system is extraordinarily complex and there is still much to learn. Under normal conditions, the system responds to triggers that stir it into action once threatened by a pathogen or toxin. When the threat is over, regulatory triggers suppress or turn off the system, returning it to its monitoring state.

In severe Covid-19 infections, the system is “hijacked” and driven into an overdrive that, in effect, turns the body’s defense system against itself. Within the complement system, the driver of dysregulation in Covid-19 has been shown to be the lectin pathway. According to one study, “early and persistent activation of complement is considered to play a key role in the pathogenesis of COVID-19. Complement activation products orchestrate a proinflammatory environment that might be critical for the induction and maintenance of a severe inflammatory response to SARS-CoV-2 by recruiting cells of the cellular immune system to the sites of infection and shifting their state of activation towards an inflammatory phenotype.”

When the lectin pathway goes into overdrive, it produces unhealthy and destructive inflammation. In severe Covid-19 infections, the resulting unrestrained inflammation damages all organ systems. Also important, in moderate or severe Covid-19, hyperactivation of the lectin pathway impairs or ablates the ability of the classical pathway to fight infection.

Real-World Answers Today

On April 4, 2023, a company funded by German Government grants, InflaRx N.V. (Nasdaq: IFRX) received US FDA Emergency Use Authorization (EUA) for vilobelimab for the treatment of severe Covid-19 in critically-ill patients. Vilobelimab is a first-in-class monoclonal anti-human complement factor C5a antibody. Part of the complement system, C5a, along with C3a, are anaphylatoxins. Anaphylatoxins are potent chemoattractants that recruit and activate a number of inflammatory cells, including macrophages, eosinophils, and neutrophils. The key takeaway here can be summarized by the InflaRx CEO, Prof. Niels Riedeman when he told me that the complement system “is involved in many diseases and the FDA recognized the great need for a new way to treat critically ill Covid-19 patients.”

Professor Riedeman believes the InflaRx approach could potentially be effective in a wide range of complement-related diseases, including the chronic inflammatory diseases hidradenitis suppurativa (HS), ANCA (anti-neutrophil cytoplasmic antibodies) -associated vasculitis (AAV), pyoderma gangrenosum (PG), and cutaneous Squamous Cell Carcinoma (cSCC).

Taking a distinctive approach to the treatment of complement-related diseases and disorders, a Seattle based biotech company, Omeros Corp., (Nasdaq: OMER) is focused on upstream inhibition of the both the lectin and alternative pathways. Its lead lectin pathway inhibitor narsoplimab is seeking FDA approval for the treatment of hematopoietic stem cell transplant-associated thrombotic microangiopathy (TA-TMA). TA-TMA has been shown to have a similar mechanism to that of Covid-19, namely damage to the cells lining blood vessels within the body. As noted earlier, this cellular damage directly activates the lectin pathway. Publications demonstrate the beneficial role of narsoplimab and lectin pathway activation in Covid-19. Upstream blockade of the lectin pathway by narsoplimab inhibits the production of anaphylatoxins and other inflammatory mediators the wreak havoc throughout the body in Covid-19, while leaving intact the infection-fighting capability of the classical pathway..

A Real Diagnostic Plan

Rapid diagnostics are essential for identification of pathogens in a timely fashion. Once a pathogen is identified, targeted therapy, which includes a well-functioning host defense system, begins.

Severe Covid-19 infection leaves patients vulnerable to life threatening sepsis. Many other pathogens and diseases also disrupt the body’s immune system causing unrestrained inflammation. It is thus important to have access to rapid diagnostics for identification not just the Covid-19 virus, but all pathogens be they viral, bacterial, or fungal.

Learning From Our Mistakes

Rather than repeating the errors of the past and investing in modalities that have not lived up to expectations, it would be wise to undertake a change in thinking and develop rapid diagnostics to identify health threats early and to restore and fortify host defenses to prevent and repair the damage wrought by those threats.

Five billion dollars well placed would go a long way to ensure a healthier future. We must learn from our mistakes – not repeat them.