David's New Book

Monday, April 6, 2020

Vaccines and Therapies for Coronavirus

I thought that this would be a good time to review the various vaccines and therapies being studied to combat the coronavirus pandemic. In such a short article, it will be impossible to review them all.  Additionally, the number under study grows substantially every day so this article might well be out of date when its published.

First, without trying to throw cold water on all your hopes, we should take a look at the odds. A vaccine or therapy that is found in a laboratory has only a tiny chance of making it all the way to approval by a regulatory agency. Once a vaccine enters the earliest stages of clinical trials (phase 1), usually in healthy volunteers to study safety and get an early read on possible immune response, the chances of ultimate approval are only around 15%.  For a therapeutic (like an antiviral drug), those odds are more like 10%. But, if a vaccine or drug makes it all the way to the last stage of clinical testing (phase 3), chances of ultimate approval go up to 75%. 

(Disclaimer – I don’t pretend to be a vaccine expert – and I’m not trying to play one on TV. Feel free to challenge my thoughts with your own research or, if you are an expert, respond to the blog). 

I’ll limit myself to only a few vaccines either already being studied in the clinic or about to enter Phase 1 clinical trials. None are farther along, hence the long timeline of 12-18 months before anything could reach the marketplace. The vaccine by Moderna that has entered phase 1 is based on mRNA. Once we knew the nucleic acid sequence of SARS-Cov-2 (today’s pandemic virus), the scientists at Modena were able to choose a portion of that sequence that encodes a key viral protein without which the virus would be unable to attack our cells. If such a vaccine could stimulate our immune cells to target that protein, we might be protected from the virus. mRNA vaccine is a scientifically “cool” technology and has promise. Not only is this an early effort, but previous mRNA vaccines have never worked to prevent an infectious disease in humans. The risk of failure is high. The same is true of the vaccine from J&J.  It seems to be based on the use of a defective adenovirus (the technology used is not publicly available as far as I can see). Once again, this approach has never worked before in humans. Nevertheless, both Moderna and J&J (with the backing of BARDA) have high confidence in their candidate vaccines. Finally, there is the vaccine announced recently by the University of Pittsburgh. To me, this has the most promise of the three I’m reviewing for you. In this case, they have purified viral proteins and impregnated a Velcro-like device with micro-needles to deliver the proteins. The microneedles inject the viral proteins just under the skin – a target known to provide for a strong immune response. This kind of approach has a good precedent for success (micro-needles aside).  If they have chosen the right proteins in the right dosage and safety is not a problem, this might work. 

I am optimistic that we will have an effective viral therapy before we have a vaccine. The first and most promising drug being studied is remdesivir from Gilead Pharmaceuticals. This drug is an analogue of the building blocks of the viral nucleic acid and stops viral reproduction dead in vitro.  It has also worked in animal models of coronavirus infection including mice and monkeys. Because remdesivir was originally studied against Ebola in clinical trials, we already have a significant safety database suggesting that safety in humans will not be a problem. Unfortunately, the drug did not work for Ebola.  But it currently is in phase 3 trials for coronavirus looking at patients with both severe and mild to moderate disease.  There is also an expanded access program available through Gilead in various centers around the world. The drug can only be given intravenously. This will be a disadvantage since, based on our experience with other antiviral drugs, it is most likely to when given early to those with mild to moderate disease.

Favipiravir, that is similar in concept and mechanism to remdesivir, is an orally bioavailable drug, and is approved for use in the treatment of influenza in Japan. Favipiravir is a rather broad- spectrum antiviral drug with activity in vitro against Ebola and SARS-cov-2.  Here, we have much less data.  But the drug is already in phase 3 trials for treatment of coronavirus infection based on it approved use for the treatment of influenza and a large safety database. 

A discussion of drugs against coronavirus would not be complete without talking about chloroquine, hyxroxychloroquine (plus or minus azithromycin). These are not direct-acting antiviral drugs.  All work by trying to improve the host response to viral infection. To say the least, the data here are incomplete and controversial. I have found four small studies using these drugs singly or in combination. Two suggest that there might be efficacy and two find no effect – especially in moderate to severe disease. Only one paper has been peer-reviewed so far. All studies are too small to allow for any sort of statistical comparison between treatment groups. Here I must agree with Dr. Fauci and others who suggest that these drugs should be reserved for those who can benefit from them – patients with lupus and rheumatoid arthritis. Panic buying will expose the public to counterfeit drugs and will deprive patients with legitimate needs of these drugs in order to live a normal life. 

All the other therapeutics are well behind the two drugs cited above. A number of companies are studying the use of monoclonal or polyclonal antibodies for the treatment of coronavirus disease. This is a promising approach that is generally well behind the antiviral drugs I noted above. Immunity will probably depend on antibodies and antibodies are probably mainly responsible for clearing the viral infection. Afflicted patients are currently being studied using convalescent plasma from patients who have survived infection.  If we can achieve sufficient antibody titers with this approach, it could save lives. It would be important, as always, to treat early. We should have an answer for these studies soon. 

I hope this brief and incomplete review puts some of the vaccine and therapeutic approaches to coronavirus infection in some perspective. For a recent, more complete (and more technical) review see this excellent article by Miguel Martinez.  Also see the analysis provided by Alan Carr of Needham.

Monday, March 30, 2020

Coronavirus - the US Debacle (Part 1)

 We have now locked ourselves down for the last two weeks.  Happily, we’re not in New York City. But we are unable to read the news every day and observe the lives of family and friends without anxiety bordering on depression. Personally, I am angry, and I want to share the source of my anger with you while emphasizing the things that we can do differently for the next emerging infection. None of what I will discuss has not been previously contemplated or foreseen. None of what is happening is a surprise, but it is so unnecessary. 

The US has failed on so many fronts

There was the lack of US intelligence during the early days of the epidemic in China and the lack of attention to the intelligence on the seriousness of the infection during January. 

There was a lack of preparedness for testing that directly led to our current situation of sheltering in place. 

We have a national stockpile that exists just for events like covid-19.  But it is woefully undersupplied and, clearly, our plans for re-supply are completely inadequate. 

We continue to underfund state and local public health facilities and workers.

Today, though, I want to briefly review the history of our approach to pandemic preparedness and the current testing debacle. 

Inspired, mainly I think, by Josh Lederberg’s report from the American Academy of Medicine in 1992 on the threat of emerging infections, experts began to seriously consider the possibility of a worldwide health crisis caused by a new (or even old) infectious agent. I was fortunate to have been asked to join Dr. Lederberg’s Forum on Emerging Infections of the National Academy in the late 1990s. We reviewed public health capabilities in the US, in other developed countries and in the developing world. We found that all were seriously underprepared to deal with anything like the kind of infectious disease we were considering. In all cases, including that of the US, we identified gaps in current infrastructure making observations on how these could be addressed.  (As a “Forum” we could not write reports or make specific “recommendations.”) After 9/11/2001 and the following anthrax attacks we reviewed preparedness for biological and chemical attacks against the US on a larger scale. These deliberations shared considerable overlap with our previous reviews of public health capacity.  We constructed models and projections of the effects of such attacks. Later, after having dealt with SARS, MERS, Ebola and Zika, the Academy released a report on pandemic planning in 2016 where improvements in global  public health infrastructure and preparedness were emphasized. All this as well as experience with an H1N1 pandemic and the emergence of avian flu led to the development of a pandemic playbook during the Obama administration. Please note that this history spanned the administrations of Clinton, Bush, Obama and now Trump – republican and democratic. 

One of the key components of preparedness is the availability of detection systems that provide early information on emerging infections that might become pandemic. In 2010 and again in 2016, reports examined progress in timeliness of identifying outbreaks and in communicating their existence.  The authors found that, overall, the world community had improved from 2000-2010 but very little since then.  Lagging regions included the Americas, Europe and South-East Asia.  (Hmmmmm).  In the 2016 Academy of Medicine report, it was recommended that the WHO take responsibility for detection and coordination of a global response. 

This brings us to covid-19 and its beginnings in China. We now know that the outbreak began in November 2019 in the Hubei region of China among customers of wild animal markets.  Local authorities were aware of clusters of pneumonia in the region but apparently were reluctant to report this. China did not acknowledge the outbreak until late December.  The WHO announced the outbreak on January 5. According to the Washington Post, US intelligence agencies had been warning about the potential of this infection since early January. (One might ask where US intelligence was during December). On January 18, Secretary Azar (of HHS) was trying to convince President Trump about the potential seriousness of this outbreak. By the third week in January, we were repatriating diplomats and others from Wuhan and the Hubei Province. On January 31 travel from China to the US was restricted to US citizens and permanent residents and their families. Somebody in the administration recognized the danger posed by this virus.  

Business Insider has published an informative timeline on testing. By January 10, the sequence of the virus was published. With the nucleic acid sequence in hand, diagnostic testing became possible. One week later, the first diagnostic testing kits were available.  By February 6, the WHO had shipped 250,000 test kits to 159 countries.  South Korea, as soon as the news of the virus from China was available, invested heavily in the manufacture of kits so that when the sequence was available, they could deploy testing to the population on a large scale. As used in South Korea, the test took about 10 minutes to complete and individuals had their results within one day. The US, for reasons that escape me, decided they would develop their own test and that it would be run at first at the CDC and later at state pubic health labs. 

Once the CDC had their test approved by the FDA, they shipped it out to the state labs – but it was faulty in spite of having passed an FDA approval process. Then, instead of immediately approving other tests for use in this emergency situation, the FDA continued to rely on its usual stodgy protocols for approving diagnostic tests. While I agree that we need the FDA to assure us that the tests are going to be accurate and useful, we also need them to have a way of accelerating their process in response to a public health emergency. They can do this but chose not to for another month. Then again, their initial approval of the CDC test was not such a good precedent either. 

The problem with this US response is that it flies in the face of basic epidemiologic principles (unless things have changed in the last 25-30 years).  The ideal way to deal with an outbreak is to identify cases and then their contacts and quarantine them for the incubation period. The first US case was reported January 22. Without widespread testing, we were unable to identify cases and therefore unable to quarantine contacts. This allowed the disease to spread throughout the US. 

South Korea instituted very wide testing of the population testing 3500 people per million population.  Even today, we are testing a measly 240 or so per million. South Korea’s test results were available within minutes to 24 hours.  Our test results still come in about 5 days later. South Korea also used cell phone localization data to track movement of identified cases and to warn those whose phones had been in the vicinity of the confirmed case. They used police to supplement health care workers in testing and searching for contacts. They were able shut down the epidemic without having to shut down the country. Of course, their epidemic started and was centered around specific church in a specific geographic area of the country so perhaps their task was a little easier than it is in our vast country. 

Like South Korea, Hong Kong, Taiwan and Singapore were all able to test widely and keep the epidemic controlled without shutting down their economies. 

One of the major problems with the covid-19 virus is that about 30% of all transmissions are from asymptomatic or minimally symptomatic people. This means that very widespread testing would be required to identify all the cases.  But other countries have succeeded anyway.

This delay in widespread testing, case -finding and contact isolation has left us with only one solution – social distancing. Our only way out of this current state of affairs involves widespread testing, case identification and contact isolation. We are nowhere near where we need to be.

In my next blog – to follow soon – I want to discuss the role that the strategic national stockpile could have played in helping to control the outbreak in the US.  And I want to explore our support for the local public health facilities and workers on the frontlines in the US and how that could have been so much better than it has been. 

Monday, March 23, 2020

Coronavirus - My Secret Hope

Coronaviruses are a large family of viruses that cause disease in animals and humans. They were discovered as a cause of the common cold more than 50 years ago.  In some studies, up to 30% of colds in children and adults were caused by these viruses. Coronavirus colds, in temperate climes, have a clear seasonality with a preference for the winter months (Figure below). They occur more sporadically in tropical climates, but there they seem to prefer spring and fall. 
CF = complement-fixing antibody

SARS or severe acute respiratory syndrome was another pandemic that started in China.  Like the current covid-19 pandemic, it originated in bats.  The intermediate host for SARS was thought to be civet cats sold in China’s ubiquitous wild animal markets. As with today’s covid-19 outbreak, the epidemic was initially hidden by Chinese officials. SARS was a more transmissible virus, where each infected person transmitted the virus to 3.5 other people compared to covid’s 2.5 others. And SARS was more deadly with a mortality rate approaching 10%.  Covid-19 looks like it will end up with a mortality rate of well under 1% globally when all the testing is finally done. This figure will depend on many factors including the capacity and quality of the healthcare systems where the epidemic is occurring. SARS ultimately infected 8000 people globally with the vast majority of cases in Asia and caused over 700 deaths.  But the most hopeful observation about SARS is its epidemic curve (see below).  The pandemic started in November of 2002 but was over by July of 2003. Why? It’s hard to believe that suddenly our ability to carry out case-finding and isolation of contacts had improved to the point where we could stop the virus in its tracks. I’m voting for seasonality.  Why didn’t it come back the next year?  Certainly not because the world was immune. I don’t know – perhaps some of you have the answer. 

Another deadly coronavirus to cause epidemic disease was MERS – for Middle East Respiratory Syndrome. Again, the origin of the virus was bats but the intermediate host appears to have been camels. The disease appeared in epidemic form in Saudi Arabia in 2012 and still causes sporadic small clusters of disease mainly in that area. Overall, there have been 2442 confirmed cases globally and 843 deaths according to the WHO. MERS is also seasonal with a peak in Saudi Arabia during the winter months and spring and fall in outside the Middle East (mainly Asia).  

The seasonality of coronavirus infections is the basis of my hope. If covid-19 goes on until July, as it well may, it will be disastrous for world health and for the global economy. But, if it is like SARS, it may then die out and not come back. Is this wishful thinking?  Yes – but based on scientific fact.  Should we hope for the best but prepare for the worst?  Absolutely. 

Practice Social Distancing – I’m talking to you, kids!

Stay Safe!  Keep your loved ones safe!

Tuesday, March 17, 2020

Coronavirus and Tetraphase

Obvious from the title, today’s blog is going to ramble a bit. I don’t apologize. 

Everyone is very excited about the start of coronavirus vaccine trials. Take a cold shower. These vaccines are mRNA based.  Once you know a gene sequence, mRNA is fairly easy to construct.  This approach to vaccine discovery is technologically “cool,” and scientifically attractive.  It has, however, never breached the species barrier in humans.  Side effects have been prominent in some trials. And then there is the problem of vaccine enhancement of disease that has been shown for a naturally occurring coronavirus infection of cats. (This has been a problem in the development of a vaccine for Respiratory Syncytial Virus in humans for decades). I would consider these approaches to be scientifically exciting, but more likely to fail than to succeed.

A recent paper from China explored risk factors for mortality among patients admitted to hospital with covid-19. Of 813 patients, 191 were included in the study (many of the rest were still hospitalized and hence had no outcome to measure). Of 191, 32 required mechanical ventilation and 31 (97%) died. Ten of the 32 developed ventilator associated bacterial pneumonia. No details on these secondary bacterial infections were provided, but bacterial resistance is rampant in China. One can only hope that, at least, they had effective antibiotics for these incredibly unfortunate patients. 

In other news, Tetraphase was sold to AcelRx for $14 million – less that cash on hand in an all stock deal. For those of you who don’t know (I didn’t), AcelRx is a company focused on sublingual formulations of drugs for pain control. Why they would be interested in a limited antibiotic like eravacycline I don’t know. This is essentially a bankruptcy without the bankruptcy filing. 

I consulted for Tetraphase for a number of years starting as eravacycline was entering its phase I trials. I even helped design their failed phase 3 trial in complicated UTI.  But the basis of that trial, and of my belief in the potential for eravacycline, was its oral bioavailability. I said from the beginning of my interactions with the company that I felt that without an oral drug, they did not have a path to commercial success. I retired just before the cUTI trial began but followed the data closely. The trial was an adaptive design with an interim evaluation to choose between two oral doses used to follow-up intravenous therapy. The interim data suggested that both oral doses were equally effective, and the higher dose was chosen for the continuation of the phase 3 trial.  As is so often the case, the interim results were misleading, and the data failed to show non-inferiority to the levofloxacin IV/oral comparator. Most of the failures in the eravacycline arm were those who received early oral therapy. To me, that signaled a failure for the drug as a whole.  Tetraphase decided to continue by carrying out a second phase 3 trial in intraabdominal infection hoping that eravacycline’s advantage of low side effects compared to Pfizer’s tigecycline would provide sufficient market for them in this single indication. That proved to be more hope that real. Eravacycline achieved $8 million in sales as of November last year. 

I’m sure I will get anonymous on my site again saying that Tetraphase got what it deserved. Maybe so.  I certainly never thought that the single indication of intraabdominal infection for an IV only drug would work commercially and I’m not sure that the analysts did either. But this is yet another nail in the coffin of investor confidence in antibiotic R&D.  And, there is more of this to come. So far, the efforts in Sweden, the UK and here in the US to take baby steps to support the antibiotic market have been (and I believe will continue to be) inadequate to bolster investor confidence. We need a bolder approach from a country or region willing to lead.

And this takes me back to the coronavirus pandemic. How important will secondary bacterial infections be in the ultimate mortality rate? Will we have effective antibiotics to combat these secondary bacterial infections.  What about the next pandemic? 

Friday, March 13, 2020

Coronavirus - an Event Foreseen

The coronavirus pandemic we are experiencing today has been contemplated by some of the world’s best scientists for at least the last 30 years. It started with a report from the National Academies in the US led by Nobel laureate Josh Lederberg in 1992 (link). Shortly after that, Josh led a Forum on Emerging Infections at the National Academies where I was one of the members. Over the next 15 years we held a number workshops and published a number of workshop summaries. Two of which explicitly dealt with public health infrastructure and the need for building surge capacity (1,2). In 2000 the report on public health infrastructure we noted the inadequate level of funding for infrastructure and the fragmented nature of the system itself where there was a constant tension between local, state and federal responsibilities and even sovereignty. We noted the frequent underfunding and understaffing of local public health agencies. Another key deficiency we saw related to our ability to mobilize adequate diagnostic testing for human health and within the veterinary and environmental areas as well. We noted the lack of sufficient ICU beds and ventilators. Finally, we identified a number of opportunities to address these gaps almost none of which have been implemented in the last 20 years. Much of this has been reiterated in more recent workshops. 

The time span between Lederberg’s initial report and today spans four administrations from Clinton to Bush to Obama to Trump – Democrat and Republican. There is plenty of blame to go around for our lack of planning and lack of investment in our pandemic response capabilities. 

In one of the many turns of my career, I left the Forum over what I perceived was their powerlessness to accomplish anything concrete to deal with our inability to develop new antibiotics during the FDA’s lost years starting around 2000. I turned to the IDSA and helped write its report on Bad Bugs No Drugs in 2004.  I think the IDSA has been responsible in part for progress at FDA and in raising awareness among decision makers. We still have a long way to go and the IDSA could still play an important role here. 

What do we do now?  For background, I recommend John Barry’s The Great Influenza
If you haven’t seen it, I highly recommend reading Tomas Pueyo’s article in Medium.com. We all need to be practicing social distancing now to preserve our ability to care for those who become seriously ill with coronavirus infection. We also need to keep pushing to get diagnostic testing available for everyone who needs to be tested and to have results available in a reasonable time. We need to be increasing our public health and private lab staffing and increasing their access to necessary supplies to carry out this function.  We need to immediately increase our ventilator supply to deal with an increasing demand across the nation. And we must provide support for all those threatened financially by lost work or lost time at school – especially those who might suffer from hunger or other serious deprivation. Everyone must be able to carry out their social distancing without fear of economic hardship. As a country and a society, we have to get our act together.  

When this is all over, we clearly need to invest heavily in planning for the next pandemic. 

Tuesday, March 3, 2020

Long Term Care - the Achilles Heel of American Healthcare

The Achilles Heel of our healthcare system is our long-term care facilities. I don’t care if we’re talking about flu, coronavirus or resistant bacterial or fungal infections. We take our most vulnerable citizens and place them in understaffed facilities with under-trained staff and where conditions may be crowded. What are we thinking?

The recent outbreak of coronavirus infection in a nursing home in Washington is not surprising – but it is scary.

Is this news?  Of course not.  The CDC has examined this question previously and provides a great deal of astounding data that you can find here.  The figures below all come from the US CDC. 

Most residents of nursing homes and residential communities are over 75 years of age with a large number being over age 80. 

Almost 70% of nursing homes and  over 80% of residential care communities are for profit organizations often part of national chains. 

The vast majority of healthcare workers in these facilities are Aides.  Each resident can expect to have 3-4 hours of care per day – mostly from Aides.  Aides, mostly, are required to have a minimum of 75 hours of classroom and practical training – not much. (By contrast, a registered nurse must have either an associate degree or a bachelor degree). Of course, during off hours like evenings, nights and weekends, staffing is often minimal.

Falls and hospital admissions are frequent.

Outbreaks of resistant infections have been documented frequently in our long term care facilities. 

My mother spent the last ten years of her life (she lived to age 97) in several assisted living facilities. They were all privately owned and one was non-profit.  But the non-profit facility distributed the wrong flu vaccine one year (not the high dose recommended for those over age 65). 

Is this something we should let the markets handle (as we mainly do now) or should we regulate these facilities more stringently? 

Thursday, February 20, 2020

Stewardship vs. Financial Incentives - a False Choice

In researching the current status of pull incentives for antibiotic research and development in Europe I came across an ongoing tension. There are those who apparently believe that we can rely on stewardship to preserve the antibiotics we already have and thus avoid the necessity of paying for new ones and those (like me) who believe that the need for new antibiotics will be without end even with good stewardship.  Some apparently believe that pull incentives are somehow an industry plot to make more money.  They may even believe that good stewardship and having even temporary pull incentives for antibiotic R&D are somehow mutually exclusive. I believe that this idea is contagious and has infected the thinking of those responsible for funding decisions like health ministers in Europe, for example. The European Public Health Alliance may be representative of this thinking. When I see this, I scratch my head wondering how rational, intelligent individuals can arrive at this conclusion and I become even more depressed about the future of our antibiotic pipeline. The choice between stewardship and financial incentives is a false one. 

First, I should state that no one, especially me, can argue that good stewardship is not crucial in our approach to preserve the antibiotics we have now as well as those I hope we will have in the future. After all, I was the first author on the IDSA and SHEA guidelines on preventing emergence of resistance in hospitals that suggested stewardship as a key tool for that purpose. But neither can one argue that appropriate use of antibiotics, and the majority of use in hospitals is appropriate, will not select for emerging resistance in time. Stewardship should slow down the process but will not prevent it. 

The other key element to stewardship, that many people tend to forget or overlook, is the idea that patients should be treated with the right doses of the right antibiotics at the right time.  We have been failing miserably at that in the modern era of new, effective and expensive antibiotics. But such an approach will mean spending more money on these new therapies (to save money in excess morbidity and mortality). 

What is needed to provide an adequate pipeline to provide insurance against the inevitable emergence of resistance is a multipronged approach.  Stewardship – in its one health entirety - including not using antibiotics at all unless clearly indicated, stopping antibiotics when they are no longer necessary, and assuring that patients are treated appropriately when they do require antibiotic therapy – is clearly one required approach. The second approach is providing both push and pull incentives where the latter are almost completely lacking today. The third may be to establish government funded antibiotic research and development that is completely non-profit where all research, clinical development, manufacturing and distribution are entirely funded by government.  An intermediate step might be to fund organizations like GARDP to partner with existing pharmaceutical (almost all small) companies that have promising new therapies in development. The ultimate goal of a publicly funded effort is to do away with the need for incentives to industry.  Whether the government funding of such an institute will be less expensive than push and pull incentives for industry is certainly not clear to me given the inefficiencies of government funding.  I know a good deal about that having carried out research at the VA for 16 years.  Don’t get me wrong – I am extremely grateful for all the support I received at the VA for all those years.  But the yearly lack of a budget, the rush to spend a capital budget at the end of the year when the budget is finally approved, and the many restrictions on what and when you could spend were all issues I did not (mostly) have to deal with in industry. 

To those stewardship enthusiasts – I am one of you. But I hope that we all realize that stewardship by itself will not be enough here. The choice between financial incentives and good stewardship is a false one.  The answer to the question of which we should pursue is all of the above.