Antibody Trial In Hospitalized Covid - 19 Patients

How do we understand the decision of the National Institutes of Health (NIH) to halt the Eli Lilly antibody treatment trial? Is it a sign that monoclonal antibodies to SARS-CoV-2, the virus that causes Covid-19, are ineffective?

The Lilly trial combined two drugs designed to interfere with SARSCoV-2 infection: remdesivir, a drug that is intended to inhibit the viral RNA polymerase, and the Lilly drug, a monoclonal antibody that is meant to prevent the spread of the virus within an infected person. The trial participants were all hospitalized volunteers with serious complications from Covid-19. The intent of the trial was to speed up recovery and prevent further progression of the disease. I do not have information regarding the exact endpoints and whether or not they include prevention of progression, the need for intensive care, and death.

Why two drugs? The presumptive benefits of remdesivir make it a drug of choice for most patients with Covid-19. A recent WHO study of remdesivir conducted in many countries found that remdesivir had no effect on hospitalized patients neither with respect to progression nor more serious disease and death. This finding did not surprise me, as the effects of the drug even at their best are described as weak to marginal. Nonetheless, most volunteers in a study of a new drug would rather receive remdesivir along with the new drug.

The NIH halted the trial because no effect on the hoped-for endpoints was observed. Patients on remdesivir fared as well (or as badly) as patients on the two-drug combination. In other words, the addition of the Lilly drug had no measurable effect. The preliminary report mentions no adverse events that occurred as a result of the two-drug combination.

Is this the end for the Lilly drug? Not at all. Drugs designed to stop virus replication should work, if they work at all, during the phase when the virus is most active. There is a phase of a few days to a week following infection when virus growth is very slow. This is followed by a second phase when virus growth is rapid and the concentration of virus particles in nasal fluids, the lung, and the intestine is very high. That is followed by a third phase in which the growth of the virus is typically contained and reduced to nothing or near nothing. Antiviral drugs should work during the incubation phase and the phase of rapid growth, but not after the virus growth is controlled.

Most people infected with SARS-CoV-2 do not experience symptoms until after the peak of virus replication. Even then the symptoms may be mild and not require hospitalization. It is only later, after the virus is no longer replicating, that the most serious symptoms appear those that require hospitalization. Treating hospitalized Covid-19 patients with antiviral drugs designed to impede a virus that is no longer replicating is the equivalent of the proverbial closing the barn door after the horse is gone.

When, then, should antiviral drugs be used? The answer is very early on in infection, or even before infection occurs. The obstacles that prevent us from using drugs early on in infection are related to how and who we test for infection. The people tested most frequently are those who have symptoms. By then the virus is already on the way out, and much of the damage the virus can do is already in progress. (There may be an exception for people who fail to make good interferon responses.)

There is a potential solution: frequent universal testing, whereby most people are tested every two to three days using tests that yield answers in 5 to 10 minutes. Such a testing regime, which I believe to be the surest way forward for contagion control, will identify those in the earliest stage of infection. Identification of an infected person should be followed by immediate treatment. Then and only then might antiviral drugs work, be they chemicals like remdesivir or monoclonal antibodies.

Antiviral drugs may also prevent infection, as is currently the case with HIV. Monoclonal antibodies are used to prevent respiratory syncytial virus (RSV) infection in infants. Antimalarial drugs are used to prevent malaria infections. The caveat is that such drugs must undergo rigorous evaluations for safety, for they are intended to be used on healthy people who are not yet infected. The safety profiles of treatments for the healthy are much more stringent than those required to treat the ill.

I suspect that Lilly will go on to test their drug in those reporting mild symptoms. The first issue of that trial design is that only some of those with mild symptoms will be detected early enough for the drug to have an effect. An even greater issue is that the great majority of those with early cold-like symptoms perhaps 80 percent or more will recover from the cold and not progress to serious disease whether given a drug or not. Therefore, any possible therapeutic benefit will be diluted by the great majority of those that will not progress in any event. Such is the life of a drug developer.

The only way I see such trials as possible is the advent of very low cost, universally available rapid virus tests to identify those recently infected. Even then, the signal to noise ratio will be low.

In conclusion, this is not the end of the line for the Lilly drug, but it is the beginning of a very long and rough road for not just their drug, but any other Covid-19 antiviral.

This article originally appeared in Forbes and is available online here: Eli Lilly Stops Antibody Trial In Hospitalized Covid-19 Patients

November 3,

2020: What Are Autoantibodies? The Latest Risk Factor For Severe Covid - 19

We know that people who are older, obese, immunocompromised, pregnant, or diabetic are at greater risk of developing severe Covid-19. Now evidence has emerged that establishes another determinant of risk something that isn’t inherited, but acquired over a lifetime. That is the inability to mount a robust interferon response.

Interferons play a critical role in defending our bodies against invading pathogens like SARS-CoV-2, the coronavirus that causes Covid-19. They function as warning signals, alerting the immune system whenever an intruder is on sight. Some people, however, develop what are called autoantibodies against their own interferons and research shows that they’re more susceptible than most to the more devastating effects of Covid-19, including death.

If antibodies are the defenders our B cells produce to battle oncoming infection, autoantibodies are defectors that do precisely the opposite. Rather than detecting and debilitating viral genetic material, autoantibodies target us A new study, made available on medRxiv but currently undergoing peer review, examined 52 patients with severe Covid-19 and found that nearly half had autoantibodies of some kind. In those most critically ill specifically the top 50 percent that number exceeds 70 percent.

None of the patients who participated in the study reported a history of autoimmune disease, but it may be the case that survivors continue to be prone to severe Covid-19 symptoms upon future encounters with the virus potentially even worse than the first time around. The flipside is that they might benefit from drug therapies for conditions like lupus. Autoantibodies are more prevalent in older adults than younger, which might explain, at least in part, why Covid-19 is, too.

If the results of this study aren’t momentous enough to impact how we treat Covid-19, at the very least they have bearing on how we diagnose and prevent it. First thing’s first, people who develop serious Covid-19 symptoms, whether they’re hospitalized or not, should be tested for autoantibodies against interferons and other relevant targets. Those who test positive, now that we know they’re more vulnerable to critical illness or death, must receive priority status for vaccinations and be cared for accordingly.

More generally, people aged 65 and older should be routinely tested for anti-interferon antibodies as part of their annual checkup. Again, those who test positive will know to be especially cautious to protect themselves from infection. After all, regardless of whether the tide of the current pandemic is turned by widespread vaccination or any other deterrent, there’s no telling how long we’ll be dealing with Covid-19 in some form particularly those most vulnerable. Any precautions we can take to prevent further spread, we should, and with haste.

The last two articles in this series on fading natural immunity to Covid-19 and fading vaccine-mediated immunity to influenza feature research that puts into perspective the timeframe of infection, disease, and potential protection. For many, all of the

MonoclonalAntibodies:TheOnceandFutureCureforCovid-19 above will tend towards the short-term, which has manifold implications for our methods of preventing and vaccinating against Covid-19.

But in the months to come, more studies will be conducted that give us a clearer understanding of the long-term effects of this disease. These in turn will force us to reconsider our methods once more. The issue of autoantibodies is one to watch, as well as one we should act to address sooner rather than later. If you have autoantibodies against interferon, you may be in it for the long haul.

This article originally appeared in Forbes and is available online here: What Are Autoantibodies? The Latest Risk Factor For Severe Covid-19