Do Abs raised against the 4 corona “cold” viruses cross react to SARs-COV2? Is this a potential explanation for the asymptomatic COV2 infections?
It is very unlikely. Humans can get reinfections with common cold human coronaviruses every season.

There may be a further slide, but what are the specific accelerations that allow vaccines and viral therapeutics to shorten the time to market? 
The fastest acceleration of development occurs when an approved symptomatic treatment can be repurposed for the treatment of COVID-19 since there is existing safety data, albeit in a different disorder/patient population. A single phase 3 study clearly demonstrating safety and efficacy in COVID-19 patients could provide sufficient information for approval. In this case, manufacturing processes are already in place but may need to be scaled up to meet worldwide need in a pandemic.
New chemical entities and biologics, not currently approved, will require a longer development time since there is no existing data supporting safe use in humans. The FDA has issued guidance for what information could be used to eliminate the need for certain studies.

In the case of COV-2, Chinese and Seattle/CDC scientists treated patients effectively with Remdesivir. Why are we talking about taking 10-15 years to target? How does the generic pharma pipeline being described here relate to 19-year-old biotechnology publications showing ease with which Coronavirus can be manipulated to target disease by animal and organ, and theoretically provide ease of discovery of therapy or vaccine?
Clearly repurposing approved drugs like hydroxychloroquine or late development stage drug candidates like remdesivir is the priority in the short term to have a significant impact on the current perspective.  The 10-15 years was to make people aware of how long it typically take to develop a drug.  As we learn more about the basic virology of the virus, scientists will likely identify new ways to attack it but it will take a while to take advantage of these new insights.  This could be very important if, like HIV, COVID-19 mutates rapidly and evades vaccination strategies or another coronavirus evolves a few years from now.

How are the current potential pharmotherapeutics that have not been approved being expedited, in regards to the clinical trial process, in regards to a potential vaccine?
The fastest acceleration of development occurs when an approved symptomatic treatment can be repurposed for the treatment of COVID-19 since there is existing safety data, albeit in a different disorder/patient population. A single phase 3 study clearly demonstrating safety and efficacy in COVID-19 patients could provide sufficient information for approval. In this case, manufacturing processes are already in place but may need to be scaled up to meet worldwide need in a pandemic.
New chemical entities and biologics, not currently approved, will require a longer development time since there is no existing data supporting safe use in humans. The FDA has issued guidance for what information could be used to eliminate the need for certain studies.

Would you please shed insight on Chloroquine and Hydroxychloroquine in regards to causing cardiomyopathies?
One of the off-target effects of chloroquine and hydroxychloroquine is blockade of a potassium channel called hERG that prolongs the repolarization interval in heart muscle and can lead to arrythmia and cardiomyopathy.  The risk of this side effect is greater at higher doses, such as the ones that were used in the Brazilian trial that was halted.

What are the differences between the SARs virus from the early 2000's and SARs-COV-2 and how would it theoretically effect the immunity period?
These are two different viruses and there is scientific evidence that they have their ancestors in coronaviruses that infect bats. Based on sequence analysis, there is about 73% overall genome homology between them.

If it attaches to ACE will an ACE inhibitor affect it?
The SAR-Cov-2 virus actually attaches to ACE2 which is a homolog of ACE, the molecular target of ACE inhibitors.  ACE2 is resistant to ACE inhibitors so it is highly unlikely that these inhibitors would directly interfere with the binding of the virus to ACE2.  One concern is that inhibition of ACE will indirectly lead to an increased expression of ACE2 which would make cells more vulnerable to the virus.  Currently, there is not enough data to determine whether this occurs, so it is too early to make a recommendation regarding the use of ACE inhibitors.

What is the difference between SARS and ARDS as it pertains to COVID? or are they the same?
SARS = severe acute respiratory symdrome and ARDS = Acute Respiratory Distress Syndrome. SARS is a qualitative term that does not define the severity of lung injury and oxygenation dysfunction, whereas ALI and ARDS are quantitative terms that clearly define the severity of lung injury and oxygenation dysfunction. Hence, coronavirus infection could provoke SARS, but SARS is not always characterized by coronavirus infection.

Presenter thoughts about existing drugs and whether they might have any efficacy as an antiviral to fight COVID-19?
Remdesivir, Favipiravir, Hydroxychloroquine, Chloroquine, Arbidol, and Lopinavir-Ritonavir were all mentioned as existing drugs that were being tested for efficacy against COVID-19.

RNA-dependent RNA polymerase inhibitors: Why was Remdesivir not approved?
It appears from the FDA’s Clinical Trial website that the remdesivir trial for EBOLA was not completed.  It was scheduled to complete in 2023 but it is possible that there were not enough EBOLA patients to complete the trial.

What phase of development has remdes gone through in MERS and SARS and how comparable are the initial data against SARS-2?
That data is not publicly available but it appears that due to the rapid spread of SARS-Cov-2 the company has been able to test it against many more patients in a very short period of time.  As you probably know, it was just approved for emergency use by the FDA based on the results of a trial conducted in collaboration with NIH.

Will ACE inhibitors or ARB’s have any affect considering the virus has spikes for ACE? 
The SAR-Cov-2 virus actually attaches to ACE2 which is a homolog of ACE, the molecular target of ACE inhibitors.  ACE2 is resistant to ACE inhibitors so it is highly unlikely that these inhibitors would directly interfere with the binding of the virus to ACE2.  One concern is that inhibition of ACE will indirectly lead to an increased expression of ACE2 which would make cells more vulnerable to the virus.  Currently, there is not enough data to determine whether this occurs, so it is too early to make a recommendation regarding the use of ACE inhibitors.

What was the rational for approval in China and Italy for the various therapeutics approved there? When speaking of Italy, its part of the EU meaning it should be under the EU approval rules. How is it approved in Italy but not all of the EU? Is it some sort of compassionate use emergency approval only in Italy?
The FDA and other global regulatory agencies allow physicians to prescribe off-label use of most medications. In March, the FDA has approved the use of chloroquine and hydroxychloroquine in teens and adults with COVID-19 "as appropriate, when a clinical trial is not available or feasible," after the FDA issued an Emergency Use Authorization. The European Medicines Agency issued a statement on April 1, 2020 that “It is very important that patients and healthcare professionals only use chloroquine and hydroxychloroquine for their authorised uses or as part of clinical trials or national emergency use programmes for the treatment of COVID-19.” Some nations within the EU have declared national emergencies allowing the restricted use of these drugs under specified conditions.

Any thoughts on Lenlizumab?
This compound was designed to treat the cytokine release syndrome which appears to trigger the Acute Respiratory Distress Syndrome associated with severe cases of COVID-19.  There appears to be a sound rationale for testing it in COVID-19 patients and the FDA has recently approved it for emergency use.

How are the current potential pharmotherapeutics that have not been approved being expedited in regards to the clinical trial process, in regards to a potential vaccine?
The fastest acceleration of development occurs when an approved symptomatic treatment can be repurposed for the treatment of COVID-19 since there is existing safety data, albeit in a different disorder/patient population. A single phase 3 study clearly demonstrating safety and efficacy in COVID-19 patients could provide sufficient information for approval. In this case, manufacturing processes are already in place but may need to be scaled up to meet worldwide need in a pandemic.
New chemical entities and biologics, not currently approved, will require a longer development time since there is no existing data supporting safe use in humans. The FDA has issued guidance for what information could be used to eliminate the need for certain studies.

What are the routes of administration for Remdesivir and Favilipivar?
Currently, Remdesivir is administered intravenously whereas Favipiravir is administered orally.

Already 30 strains of covid-19 have been detected. Any preliminary results on the viral resistance of different strains upon remdesivir and other drugs?
There is no publicly available data on the development of resistance to remdesivir.

Are there any reports/investigation demonstrating differences among races in terms of heterogenicity?
There is preliminary data from the CDC indicating that the death rate among the Black and Hispanic populations in the U.S. is greater than in the Caucasian population.  There are many socioeconomic factors that likely contribute to this finding and they are the subject of active investigation.

Has there been any indication of patients who are on current HIV therapy you mentioned , not becoming infected with COVID or having mild s/s ?
According to the World Health Organization, “At present there is no evidence that the risk of infection or complications of COVID-19 is different among people living with HIV who are clinically and immunologically stable on antiretroviral treatment when compared with the general population.”

Placebo controlled studies are ethically correct?  Given the current situation?
Placebo controlled studies are acceptable when there is no proven effective intervention for the condition under study, or when placebo is compared against an investigational treatment added on to established treatment. This includes trials of treatments shown to be efficacious in some populations but where the data cannot be extrapolated to the population of interest. Use of placebo in this case is typically not ethically controversial. Currently, there is no proven effective treatment for COVID-19 so patients randomized to placebo are receiving this along with standard of care. These patients are exposed to the same risk (unproven efficacy) as those who are administered the experimental treatment.

Standard trials? Epidemics provide political justification for research funding, focused on vaccines. How does product development really translate into affordable and safe use? If I am not mistaken vaccines for tuberculosis were not being used in low income countries where TB was part of the differential diagnosis. Many of the people in Italy who died from COVID north of Milan had been treated for TB. Under the CDC/NIH approach to disease definition, common pathogens are removed from Medical research and clinical protocols. Tests are simply not made part of the differential DX (for TB as one of many examples)… while useful vaccines are not made available. Given the CDC approach to letting COVID testing go "wild", how can a vaccine be proven successful in terms of real human health data? If past epidemics set the stage for standards in this case, why would we expect that vast investment in a vaccine leads to good use, rather than control over legal rights of people who just want to contribute to society?
These are complex questions involving science and society, writ large, and are the subject of discussions that require further thought than can be provided here. Pandemics are treated as “Black Swan” events that trigger funding for research into symptomatic and preventive treatments. This approach is not ideal given the increase in new pandemics over the past 2 decades. This provides a good argument for consistent  planning for new pandemics and perhaps additional research funding “universal” viral vaccines. Despite current news stories, the FDA’s approach to approval of symptomatic and preventive treatments has not gone “wild.” Efficacy and safety will be required to approve new treatments before widespread use. The more rigorous clinical trials (randomized allocation, blinded, defined dose range and medically relevant endpoints, etc.) will have the best chance of providing meaningful information. Emergency Use Authorizations by the FDA are specific in terms of use and are temporary. Compassionate use authorizations also require specific conditions when they are granted.

I would like to know your opinion about the correlation of ACE2 levels in patient with diabetes or taking antihypertensive drugs and the mortality of COVID.
While there is increasing evidence that pre-exisiting conditions such as hypertension and diabetes seem to increase the risk and severity of SARS-Cov-2 infection there is not enough data available to establish a clear correlation between these factors and the mortality of COVID-19.  There is pre-clinical evidence that treatment with some ACE inhibitors can increase ACE2 expression but the consensus among clinical experts is that there is not enough data to make recommendations about altering drug treatment strategies for hypertension or diabetes.

Why are the clinical trials required blinding or placebos to strengthen the data, reduce the impact on getting less useful information?
The use of placebo controls, randomized allocation and blinding are the most effective methods for eliminating unintentional bias that can occur in a clinical trial and strengthen validity of the study results.

Are there any Phase 3 Favipiravir trials underway as well?
Not in the U.S.  There is a Phase II, Open label, randomized trial in patients with COVID-19 that is designed to enroll 50 patients.

Can you say something about the mutation rate of the virus genome, is there a proof-reading mechanism, and how this would impact longevity of a vaccine?
Coronaviruses are unique among all RNA viruses because they encode a protein with ExoN activity.  This nsp14-ExoN is essential for replication fidelity, and likely serves either as a regulator of a more complex RNA proofreading machine, a process previously unprecedented in RNA virus biology. Developing vaccines is very complex and it is not only about virus genome varability. 

Do you think 28wk clinical trial for vaccine ending Nov 2020 (before flu season) suffice when others go 1yr(+)?
All of the novel SARS-COV-2 vaccines are in Phase 1 or 2 trials. The ascertainment increase in IgG titer from baseline, antibody titer and the percentage of subjects who seroconvert will be determined in 4-8 weeks and if those endpoints are met, Phase 3 studies will start. FDA guidance requires 28 weeks of safety data included with submission of the Biological License Application and longer-term data from those subjects prior to final approval. The FDA could grant emergency approval before Phase 3 under an Emergency Use Authorization but this would come with specific restrictions. All requirements are described in the FDA Guidance Clinical Data Needed to Support the Licensure of Pandemic Influenza Vaccines.

Can any of the panelists contribute to the question of addressing the possibility of medical devices regulating the cytokine storm and increased inflammatory response syndrome as an adjunct therapy, specifically relating to NETs?
“On April 10, 2020 the FDA issued an emergency use authorization for a blood purification system to treat patients 18 years of age or older with confirmed Coronavirus Disease 2019 (COVID-19) admitted to the intensive care unit (ICU) with confirmed or imminent respiratory failure. The authorized product works by reducing the amount of cytokines and other inflammatory mediators, i.e., small active proteins in the bloodstream that control a cell’s immune response by filtering the blood and returning the filtered blood to the patient. The proteins that are removed are typically elevated during infections and can be associated with a “cytokine storm” that occurs in some COVID-19 patients, leading to severe inflammation, rapidly progressive shock, respiratory failure, organ failure and death.” {Source}

Could you explain further how the virus is pH dependent?
COVs can enter at the cell membrane and/or via endocytic pathways. In the endosome there is an acidic pH that is crucial for some proteases activation that are involved in cleaving the Spike protein to induce fusion.

If an available medicine in market to be repurposed to check its efficacy against covid 19, does it need to go into the same from the scratch drug dev. clinical phases or can be shortened for the sake of time? Take into account that those meds do not have such toxic effects?
Repurposed drugs will not undergo the typical development process. One (or 2) Phase 3 trials in COVID-19 patients will suffice. The FDA will want a determination that the efficacy results are reproducible and safety data from COVID-19 patients who may respond differently from other patients previously studied in prior NDA submissions.

Shouldn’t all clinical trials be required to use blinding or placebos? Secondly, why are these trials not monitored as they are propose to reduce the impact on the resources available on less than significant studies?
These trials should be randomized, blinded and controlled particularly if the sponsor is seeking approval based on only 1 study. All trials must be monitored to comply with Good Clinical Practice requirements.

With SARS and MERs being endemic to certain areas, what properties of Covid-19 produced a worldwide pandemic?
The existence of infected individuals with no clinical symptoms who can shed the virus and be contagious to others.

Which "Viable 3 questions" should we ask about the vaccine studies rather than asking when the vaccine will be available, 18/24 months?
Many sources mention “having” a vaccine in 18-24 months. The validity of a statement like this depends upon one’s definition of “having.” We should be asking how long it will take to identify a potentially viable vaccine candidate, when will confirmatory studies start and how long must those studies be in order to approve the vaccine as safe and effective before we start widespread treating hundreds of millions of people.

Do asymptomatic persons seroconvert?
Asymptomatic subjects may carry the virus and thus seroconvert in a vaccine trial. From the FDA guidance on Clinical Data Needed to Support the Licensure of Pandemic Influenza Vaccines: “Appropriate endpoints may include: 1) the percentage of subjects achieving an HI antibody titer ≥ 1:40, and 2) rates of seroconversion, defined as the percentage of subjects with either a pre-vaccination HI titer < 1:10 and a post vaccination HI titer > 1:40 or a pre-vaccination HI titer > 1:10 and a minimum four-fold rise in post-vaccination HI antibody titer. In a prepandemic setting it is likely that most subjects will not have been exposed to the pandemic influenza viral antigen(s). Therefore, it is possible that vaccinated subjects may reach both suggested endpoints. Thus, for studies enrolling subjects who are immunologically naïve to the pandemic antigen, one HI antibody assay endpoint, such as the percentage of subjects achieving an HI antibody titer > 1:40, may be considered.”

How contagious are people after covid recovery?
We don’t know; important question but no clear answer.

Could plasma donation for antibody transfer reduce the immunity of the donor? 
Unlikely. The antibodies are just the end products of immune cells stimulated to produce them.

Are the attrition rates for general drug development or for infectious diseases. Do you know attrition rates for vaccines?
Attrition rates shown were for drugs. The attrition rate for vaccines is similar at ~6%.

Is COVID-19 a more severe disease in people with HIV or are individuals own ART protected against COVID?
This is obviously a concern for people who have HIV, since HIV is known to be an immunosuppressive illness. However, as the guidance notes, the limited data currently available do not indicate that the disease course of COVID-19 in person with HIV differs from that in persons without HIV. And that's particularly the case for people who are stable on antiretroviral therapy (ART). However, this is a very interesting question and studies are underway to test this.