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The Link: Special Issue

March 2020

The Challenges of Caring for COVID-19 Patients & Vaccine Considerations


Dr jackson.jpg

Mary Anne Jackson, MD | Interim Dean and Professor of Pediatrics - UMKC School of Medicine | Medical Editor, The Link Newsletter


Christopher J. Harrison, MD, FAAP, FPIDS | Professor of Pediatrics, UMKC School of Medicine

This alert identifies the newest updates on COVID-19 and the immediate, multi-prong proactive response that is necessary as clinicians respond to the challenge of caring for patients, not only with COVID-19, but with other serious diseases that do not take a vacation just because COVID-19 is here.

What are the major challenges?

SARS-CoV-2 testing capacity and turn-around time for test results continues to be inadequate, so the well-known infection prevention and public health strategies we would use for any infectious disease (case identification, isolation, quarantine, and contact tracing) have been abandoned in many areas like King County, Wash. and Sacramento County, in Calif., realizing that community transmission is ongoing. Increasing test availability each day means we will see an uptick in cases and will make it more difficult initially to see flattening of the curve. 

Inadequate PPE supplies require restrictions to conserve use for symptomatic cases. Although it appears that transmission is very low in asymptomatic people, we think that infected but mildly ill individuals may be prime vectors for transmission. Thus, health care workers should continue to screen patients for mild symptoms prior to their visit. Especially now as mathematical models predict the surge of cases, planning turns to ensuring intensive care bed and ventilator capacity, anticipating a weekly doubling of cases over the next month. Given that SARS-CoV-2 is primarily transmitted by droplet, the newest CDC guidance recommends droplet precautions along with gown, gloves, and eye protection. So, patients can be evaluated in a private examination room with the door closed. Airborne infection isolation room (AIIR) as needed for measles, varicella and tuberculosis is no longer required except for aerosol generating procedures, e.g. intubation. CDC does NOT consider the collection of a NP, mid-turbinate or OP swab as aerosol generating. 

What are the major unknowns?

Disease epidemiology is still not completely elucidated; even now we are making decisions without robust data to guide us. We don’t yet know how many people have been infected or the entire spectrum of clinical manifestations. The estimated case fatality rate is based on limited data with potential selection bias, so may be overestimated. Most detected COVID-19 cases so far are the sickest; most but not all of those are individuals with underlying medical conditions or seniors with co-morbidities. Country-to-country differences in case fatality rates are also important. In Italy, which has the highest case fatality rate in the world, factors that appear to increase COVID-19 mortality risk include:

  1. The Italian population is the second oldest in the world.
  2. Intergenerational socializing is common.
  3. They have a high rate of smoking.
  4. They have the highest of antibiotic resistance rate in Europe, thereby increasing risk for death caused by bacterial superinfection. 

Current evidence suggests that the early interventions flatten the curve (South Korea, Singapore, Hong Kong). Even in Italy where one northern city implemented a strict lockdown early in the outbreak, cases were fewer and rose more slowly compared to other cities. So social distancing (enforced actively), along with enhanced hygiene and strict quarantine of infected persons seems our best chance to flatten the curve in the US. 

But how long will this combination strategy be needed? As of March 24, only 13 states have effectively locked down and, in many where the governors have not acted, mayors have enacted directives for their counties. But if not all contiguous counties participate, there will be travel between counties that do not have a “shelter in place” into counties desperately trying to ensure effective action. And now the news that some New Yorkers trying to evade shelter in place orders are flying to Florida, provoking Florida’s governor to consider 14-day quarantine for anyone flying in from New York. The Korean data is that 3-4 weeks of lock down can be sufficient if started soon enough (before the sharp rise in the curve). But China is showing us that 3 months may be needed (or more), even if intervention is draconian, if not started until the curve is rising quickly.   

What are the areas of focus beyond PPE and testing?

We have several national surveillance systems for influenza, and they are being harnessed to survey for SARS-CoV-2 but have met logistic and regulatory hurdles. Yet even within the existing influenza surveillance systems, results are not usually available for 4-6 months after the start of the season. Real-time results have not been possible except for selected areas and age groups, and this for influenza which has easy and plentiful testing. Even while COVID-19 surveillance samples are being planned and collected, testing lags way behind, so data will continue to expand but at a slower than ideal pace. 

What is critically needed at this point is a seroprevalence study in a robust sample of our population. This is to some extent a view in the rear view mirror of who is immune and can go about their usual business without fear of infection or spreading to others. To tell us how many have been infected, we need to continue to define the prevalence over time. Here again, currently, no standardized specific serologic test is available but the CDC has just developed and is pilot testing serology tests.  

Now we need to confirm which medical treatments may be effective and can be implemented quickly. 

  1. The two initial as yet unpublished studies of hydroxychloroquine were poorly powered and not scientifically rigorous. Ongoing controlled studies in some cases include azithromycin as combination therapy. These drugs aim to block host cell machinery that the virus uses to replicate. 
  2. Results of ongoing studies of a broad-spectrum antiviral used in Ebola treatment, intravenous remdesivir, may be available by early April. Another antiviral used in Asia (favipiravir) still requires more research before we know if it improves outcomes.
  3. A plasma product from those recovered from COVID-19 has shown promise in limited use; the first infusions just took place in New York, so we hope for answers soon. Further development of other similar agents, e.g. concentrated antibodies, may be available in 9-18 months
  4. Because increasing evidence for an IL-6 driven inflammatory over-response is associated with increased morbidity and mortality, drugs like tocilizumab and sarilumab, both IL-6 inhibitors, were studied in small studies with promising initial results, e.g. improvement in acute respiratory distress syndrome in severely ill patients. 
  5. Early data suggest that certain drugs used frequently by the elderly could theoretically enhance COVID-19 disease, e.g. ACE inhibitors and ARB classes of drugs, by increasing unoccupied receptors that SARS-CoV-2 uses to attach to and enter our cells. However, it is very clear that those drugs used to treat heart failure, hypertension and ischemic heart disease are life saving and the American Heart Association and American College of Cardiology have issued guidance to say these drugs should not be discontinued. 

12 to 18 months for a COVID-19 vaccine – why so long?

Some say pandemic COVID-19 may not settle down for good until we get an effective vaccine, but caution that it could take 12 to 18 months or longer - a long time considering the <8 months needed to release the 2009 pandemic H1N1 influenza vaccine. So why so long? 

  1. For influenza, an existing process was used. With pnd2019 H1N1 vaccines, there was no need for phase 1 studies. We had an established process and manufacturing chain in place. We simply substituted the new H1N1 for seasonal H1N1 and made buckets of vaccine that was tested by existing federal funded infrastructure (CM was a test site) and was available in <8 months. 
  2. No established marker of protective immune status. The same surrogate markers of protection that had been used for generations for seasonal influenza vaccines worked for the new H1N1. There was no need for new efficacy studies – i.e. vaccinating people and then seeing if they were protected from natural exposure to the virus. The results showed the pandemic influenza vaccine would work at least as well as seasonal vaccines. 
  3. Novel pathogen vaccines usually take 5-10 years. Making millions of doses of a new vaccine requires adding laboratories and factories that undergo major modifications, training workers, managing quality control and preventing contamination. But even before that, usually small vaccine lots are carefully and safely produced to test in animals and then humans. 
    • Phase 1. In dozens of adults and subsequently children, at least 4-6 weeks post-vaccination are needed to show short term safety and another 3-6 months to show the vaccine induces immune responses. But if we don’t know what immune responses are really protective how do we judge immunogenicity? And do we need another 6-9 months to see if the “protective” immune responses persist? 
    • Phase 2 and 3. Confirming results in thousands of adults/children and seeking undetected safety issues that were missed in the early phase studies (remember the first rotavirus vaccine) usually requires 3-5 more years. Data are then submitted to FDA for multi-month review. If approved, 4-6 months are needed to ramp up production and assure distribution.
    • The regulatory processes can be condensed to weeks/months instead of years in an emergency, but there are limits on how much production, packaging and distribution can be hurried.   
  4. Second safety facet. For respiratory virus vaccines, surveillance for vaccine induced immune responses that worsen disease, like with the first RSV vaccines, is needed too. 

Lessons learned

On the plus side, coronavirus vaccine work started decades ago. Remember, COVID-19 disease virus is really SARS-2. SARS-2 sounds familiar because SARS-1, another novel Asian mutated animal coronavirus, caused pandemic concern 20 years ago by hopping into humans, but SARS-1 was not readily community-transmitted. More recently MERS virus, a Middle East animal coronavirus, caused pandemic concern, but also did not exhibit sustained community transmission. Intense efforts at producing vaccines for both were started but abandoned due to lack of funding, or we might be farther along for a COVID-19 vaccine. So, successful vaccines for known human (and animal coronaviruses) remain elusive, despite discovery that the “spike” (virus surface protrusions that attach to and facilitate virus entry into the host cell) contained key antigens. 

How to begin?

The simplest vaccines are injectable deactivated organisms produced by proven and well-established manufacturing processes; however, it is clear from SARS-1, MERS and animal coronavirus vaccine attempts that simple killed vaccines don’t work. Partially successful coronavirus vaccines have been live attenuated vaccines (similar to intranasal influenza vaccine) or subunit or “spike”-containing vaccines (like HPV or pertussis vaccines). 

Novel approaches

The first candidate in US trials as of March 15, is a messenger RNA (mRNA) vaccine. Messenger RNA can be produced quickly in massive quantities with current technology and is relatively inexpensive to produce. When injected in the proper conditions, it uses host cell machinery to produce thousands of copies of the peptide (aka COVID-19 antigen) for which the mRNA is the template. It uses our own bodies to produce the final vaccine “product”. mRNA vaccines have not had safety issues and have worked experimentally in animals for other viruses. There are least 11 other candidate vaccines now or soon to be in overseas or US trials. So, don’t despair, but be patient. 

In the meantime, prescribe and utilize social distancing and continue the excellent infection prevention practices that we all know about.  Because things change daily, it remains important to maintain the flow of important information to help us make better decisions.