COVID-19 ANTIBODY VERSUS DIAGNOSTIC TESTING

One of the main challenges in response to the COVID-19 pandemic has been testing. Diagnostic tests can confirm if someone has an active COVID-19 disease, whereby antibody tests confirm if someone previously had the disease and has developed immunity. Numerous diagnostic tests have been developed to improve the accuracy, shorten the time required to produce results, and make the process to obtain a sample less invasive. Abbott has produced a diagnostic test that requires only 5 minutes and a sample from the nostril, which is faster and less obtrusive than previous tests obtained from nasopharyngeal samples. Diagnostic tests allow medical providers to make a differential diagnosis, recommend self-quarantine and pursue supportive care measures. Recent CDC statistics estimate nearly 5 million people have been tested for COVID-19 in the United States.

Another significant type of testing is serology testing. Dr. Redfield, the CDC Director, has said that these tests will be an essential part of the United States plan to move forward. The purpose of serological tests is to determine the presence of antibodies in the blood. Antibodies develop as part of an immune response to infection, as opposed to diagnostic testing which aims to detect the presence of a disease-causing agent, known as an antigen. Serological tests can provide insight into how many asymptomatic people have been previously exposed to the virus and have developed antibodies to fend off infection, and possibly prevent new infections. The presence of these antibodies may suggest people could return to work in a safe manner.

The National Institutes of Health (NIH) has launched a study utilizing antibody testing in over 10,000 people to quantify undetected cases of COVID-19. Quantifying asymptomatic cases and those that have immunity may shed light into the degree of virility and transmissibility of the virus. Therapeutically, serological tests may be utilized to determine who can donate blood that can be used to manufacture convalescent plasma as a possible treatment for critically ill patients with COVID-19.

Epidemiologists often reference “herd immunity” when discussing communicable diseases. Herd immunity is an indirect protection from infectious disease that occurs when a large percentage of a population has become immune to an infection. Thus, providing a measure of protection for individuals who are not immune. How contagious a virus is determines what percentage of people need to be immune to achieve herd immunity. To put it into context, measles requires a minimum of 92% of a population to be immune to prevent its spread. Laboratory data has indicated SARS-CoV-2 is not as contagious as measles. Thus, according to researchers at Johns Hopkins University, if 70% of a population is immune to COVID-19, herd immunity may be achieved.

There are still several questions that remain regarding antibodies and immunity against SARS-CoV-2. The length of immunity is unknown and may play a crucial role in establishing guidelines for reopening the economy, relaxing social distancing requirements, better understanding the immune response to the virus, and vaccine development. Length of immunity can vary widely as observed previously with other viral infections. For example, immunity to the common cold can be as short as a few months, while protective antibodies against the virus that caused the SARS outbreak in 2003 are still present in people almost two decades later. The length of immunity will help to model a potential vaccine schedule like an annual flu shot or a tetanus vaccine administered every ten years.

The immune system develops several different types of antibodies in response to an infection; however, it remains to be determined which antibodies should be the primary focus. IgM is typically the first antibody produced by the immune system, followed by IgG. Testing for IgM can indicate a more recent infection, while the presence of IgG may be a better indicator of sustained immunity. A potential area of concern is that if a person is tested shortly after coming in contact with the virus and has not yet had time to develop antibodies, test results may indicate a false negative. It is not currently known how long antibodies will remain present in the body after the infection has been resolved.

The FDA has authorized an expedited process for the many antibody tests in an effort to increase accessibility. Only four of the -more than 90 antibody tests now on the market in the U.S. have gone through vetting through the Emergency Use Authorization (EUA) process. The biggest concern is that tests may not have a high level of specificity; they may return false positives when someone has developed antibodies for other viruses. Due to the variables and current limitations of antibody tests, the FDA has issued recommendations to health care providers -not to use these antibody tests as the sole basis to diagnose COVID-19, but rather as information about possible prior exposure.

In the constantly evolving battle against COVID-19, serological tests will provide an essential tool for scientists and medical professionals as more data is compiled and tests become more refined.

https://www.medicinenet.com/what_antibody_testing_tells_us_about_covid-19-news.htm?ecd=mnl_day_042120

https://covidtracking.com/data/us-daily

https://www.medicinenet.com/coronavirus_herd_immunity_antibody_test_accuracy-news.htm?ecd=mnl_day_042420

https://www.healthline.com/health/serology

https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/testing.html

https://www.fiercebiotech.com/medtech/fda-officially-authorizes-its-first-serological-antibody-blood-test-for-covid-19

https://www.fda.gov/medical-devices/letters-health-care-providers/important-information-use-serological-antibody-tests-covid-19-letter-health-care-providers

Impact of Coronavirus on Prescriptions

During the Coronavirus pandemic insurance companies and pharmacy benefit managers have executed many allowances for prescriptions, including relaxation of “Refill too soon” edits, 60-day extension of existing prior authorizations, and allowing retail 90-day prescriptions. This could lead to increased costs.

However, as the entire medical community focuses on the COVID-19 pandemic, volumes of other types of medical visits and prescriptions have dropped dramatically. According to a survey taken by Piper Sandler, a financial services company located in Minneapolis, patient volumes are down 65% and may still be down by about 12% one year from now.

In addition, more than half of all office visits will be via telemedicine through the foreseeable future. Telehealth visits are expected to be as high as 54% of all visits, which is more than a 5-fold increase over pre-COVID-19 numbers. This will help some practices, but is still contributing to a furlough of some medical staffing.

Along with an unprecedented drop in patient volumes, prescription writing dropped by 47% in March, as patients refrain from normal office visits. It is expected to be down by a similar percentage in April. The number of prescriptions for some drugs have declined significantly, while others appear to be holding steady. Total prescriptions for drugs for acute use, such as headaches or heartburn, have plummeted by 28% since February. In contrast, chronic disease therapies, such as those for diabetes or mental health, are doing well, with weekly scripts even growing 2% at the end of March as compared with early February.

Vaccines saw the most decline, most likely because people are concerned about going to doctor offices and pharmacies for vaccinations to address viruses and diseases they do not even have. Other medications that have declined are ophthalmic preparations such as Restasis, and IBS-Constipation medications such as Linzess. Meanwhile, the autoimmune market, HIV and anticoagulants have so far not seen any changes.

Biopharma is not immune to this phenomenon.  The current lockdown is not only hurting clinical trial enrollment, but also delaying regulatory timelines for those drugs that are nearing an approval.  New drug marketing has also been affected because pharmaceutical representatives are unable to call on doctors due to COVID-19 social distancing and quarantine guidelines; for example, the launch of Bristol Myers Squibb's long-awaited Multiple Sclerosis drug, Zeposia, has been postponed.

The coronavirus impact as it relates to the pharmacy benefit is changing by the hour.  The PBIRx team of clinical pharmacists is constantly researching to keep our clients and partners abreast of the newest information so that they can make knowledgeable decisions.

https://www.healthcaredive.com/news/doctors-say-covid-19-has-slashed-patient-volumes-made-finances-shaky/575876/

https://www.fiercepharma.com/marketing/retail-scripts-vaccines-and-acute-drugs-decline-sharply-amid-covid-19

https://www.fiercepharma.com/marketing/biopharma-s-drug-launch-trajectory-bent-by-covid-19-but-some-maybe-more-resilient

COVID-19 Vaccine

Recent statistics in the United States reveal nearly 700,000 confirmed coronavirus cases and over 36,000 casualties. Mitigation strategies and an improved awareness of the highly transmissible nature of COVID-19 have over 95% of Americans on orders to stay at home. While therapeutic options to treat infected people continue to be investigated, it is apparent that an effective vaccine is needed to prevent people from contracting the deadly virus and enable the world to return to a sense of normalcy.

Prior estimates from Dr. Fauci, the director of the National Institute of Allergy and Infectious Diseases, for the development and approval of a potential vaccine were 12 to 18 months, which would be much faster than the typical time required for vaccine development. Data has shown that the rate at which SARS-CoV-2, the virus that causes COVID-19, mutates is not as rapid as the seasonal influenza virus. This is encouraging because if a vaccine becomes readily available within the next couple of years, it could have a prolonged effect by eliminating future cases. There are currently over 70 vaccines in various stages of development globally.

The Coalition for Epidemic Preparedness Innovations (CEPI) and the Biomedical Advanced Research and Development Authority (BARDA) have contributed hundreds of millions of dollars to develop and facilitate the costly process of finding a safe and effective vaccine. In addition, thirteen drug companies have agreed to collaborate and share their proprietary molecular compounds with a COVID-19 therapeutic accelerator launched by the Bill and Melinda Gates Foundation in an effort to expedite the development, manufacture and delivery of vaccines, diagnostics and treatments for COVID-19. Most notably, Novartis, Boehringer Ingelheim, Eli Lilly, Gilead, GlaxoSmithKline, Johnson & Johnson, Merck, and Pfizer are engaged in the race to develop the vital vaccine. GSK and Sanofi have joined forces in an unprecedented collaborative effort with the hopes that combining their resources and technology will have a synergistic effect.

Among the vaccine technologies under consideration are whole virus vaccines, recombinant protein subunit vaccines, and nucleic acid vaccines. Any drug or vaccine must go through three phases of clinical trials before FDA approval. There are two vaccines currently in Phase 1 of clinical trials in the United States, with many more being evaluated around the world. The purpose of Phase 1 trials is to determine the safety profile in healthy adults.

Moderna Therapeutics rapidly developed an early prospect for clinical trials on March 16^th, just 42 days after the genetic sequence for SARS-CoV-2 was released. Their candidate, known as mRNA-1273 is a novel lipid nanoparticle (LNP)-encapsulated mRNA-based vaccine that encodes for a stabilized spike (S) protein of SARS-CoV-2. In their Seattle based trial, forty-five healthy adults will be enrolled into one of three cohorts and will receive two intramuscular injections four weeks apart to assess the safety and reactogenicity of mRNA-1273, with subsequent evaluation at regular intervals over the course of 12 months. It is important to note that the biotechnology being utilized has been in existence for nearly 30 years, yet has never produced a viable, FDA-approved vaccine for any human disease. This highlights the fact that laboratory and animal studies cannot be extrapolated to determine appropriate use in humans.

Inovio Pharmaceuticals announced on April 6^th that the FDA accepted its application for INO-4800, its DNA vaccine candidate. DNA medicines are made of optimized DNA plasmids which are synthesized or reorganized by computer sequencing technology with the hopes of targeting a specific immune response. Preclinical data has shown positive immune response results across numerous animal models. The Phase 1 study of INO-4800 will enroll up to 40 healthy adults in Philadelphia and Kansas City where they will also receive two doses four weeks apart. Initial immune responses and safety data are expected to be available by late summer. Inovio plans to have a million doses of the vaccine manufactured by the end of the year for additional trials and emergency use, pending regulatory approval and funding.

Novavax announced on April 8^th that it has identified an “ideal” COVID-19 vaccine candidate and is set to begin their first clinical human trial in May. The candidate, known as NVX-CoV2373, has demonstrated an ability to produce immune responses and high levels of antibodies against COVID-19 in animal studies. NVX-CoV2373 uses antigens derived from the coronavirus spike protein to stimulate an immune response to provide protection against COVID-19. Novavax is working with another firm, Emergent BioSolutions, to expedite the process and they expect to have preliminary human data by July.

While vaccines undergo the beginning stages of development, treatment options continue to evolve with data from around the world. Researchers in the New England Journal of Medicine concluded that treatment with Remdesivir in a clinical trial of 53 people resulted in clinical improvement in 68% of patients. Rates of mortality, hospital discharges, and the ability to discontinue ventilator use were the factors considered in determining clinical improvement. No new safety concerns were observed, which is encouraging for an uninhibited approval process.

Hydroxychloroquine continues to be a top therapeutic candidate for the treatment of COVID-19 with clinical trials underway in nations worldwide. However, a trial studying use of high-dose and low-dose chloroquine in hospitalized patients in Brazil resulted in premature termination of the high-dose arm due to safety concerns after only 81 patients were treated. One of the most concerning adverse effects of chloroquine is QT prolongation and arrythmia, which is an irregular heart rate and may be fatal.  Azithromycin, an antibiotic often used in conjunction with hydroxychloroquine to treat COVID-19, is also known to produce QT prolongation in patients with certain cardiovascular disorders. For that reason, the American College of Cardiology, American Heart Association, and Heart Rhythm Society issued a joint statement outlining critical cardiovascular considerations for use of hydroxychloroquine and azithromycin for treatment of COVID-19.

Further studies and anecdotal reports of hydroxychloroquine treatment of COVID continue to be presented in the news. Reports include individuals such as a lawmaker, a New Jersey healthcare provider, and a former NFL player who believe that hydroxychloroquine helped them defeat the virus. Overall, these reports have been both positive and negative. A small study in France in eleven  consecutive patients failed to show an improvement of symptoms  and reduction in viral load after being treated with hydroxychloroquine (600 mg per day for 10 days) and azithromycin (500 mg day 1 and 250 mg days 2 to 5) and discusses a patient who experienced QT interval prolongation before treatment was discontinued. Another newly publicized study in Shanghai in 150 patients reported hydroxychloroquine failed to clear the virus better than standard care but patients receiving it did show improvement in clinical symptoms and a reduction of an important inflammatory marker in the blood. Side effects observed in this study were mostly mild and reported in half of the patients that received treatment. This prompted the study investigators to suggest that hydroxychloroquine’s potential effects against COVID-19 may be its anti-inflammatory mechanisms.

 A large scale study, titled “the Outcomes Related to COVID-19 treated with Hydroxychloroquine among In-patients with symptomatic Disease study” (ORCHID Study), in Tennessee has begun to evaluate the effects of the drug in a blinded, placebo-controlled randomized clinical trial of over 500 adults. The study is enrolling patients currently hospitalized with COVID-19 or in an emergency department with anticipated hospitalization. The National Institutes of Health (NIH) is overseeing this study, as well as one to evaluate Remdesivir in a similar manner. This is a significant development because prior studies were not conducted in a blinded, placebo-controlled randomized nature. These factors are indicative of a more valid scientific approach and are more likely to have an impact on FDA approval than small anecdotal type reports that were previously reported.

Convalescent plasma and hyperimmune globulin from individuals who have fought off the virus and have developed antibodies remain a viable treatment option. The blood obtained from these people may be administered to critically ill patients diagnosed with COVID-19. The FDA is leading a collaborative effort with partners from the pharmaceutical industry, academic institutions, and government partners to implement a protocol that would involve the MAYO clinic and the American Red Cross to collect and distribute plasma to patients around the country.

As the number of confirmed cases and deaths attributable to COVID-19 continue to mount, researchers continue to work diligently to evaluate which treatment options prove to be the most safe and effective. Vaccines remain the only way to eradicate such a disease and from having catastrophic effects in the future.

https://www.nationalgeographic.com/science/2020/04/why-coronavirus-vaccine-could-take-way-longer-than-a-year/

https://www.nejm.org/doi/full/10.1056/NEJMp2005630

https://clinicaltrials.gov/ct2/results?cond=COVID-19&term=vaccine&cntry=&state=&city=&dist=&Search=Search

https://bgr.com/2020/04/07/coronavirus-vaccine-update-who-wants-cures-to-be-widely-available/

https://nypost.com/2020/04/08/novavax-to-start-trial-for-ideal-coronavirus-vaccine-candidate/  

     

https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-blood-purification-device-treat-covid-19

https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-coordinates-national-effort-develop-blood-related-therapies-covid-19

https://www.beckershospitalreview.com/pharmacy/gilead-boosts-remdesivir-production-now-has-1-5m-doses.html

https://www.beckershospitalreview.com/pharmacy/13-drugmakers-form-consortium-to-find-covid-19-treatments.html

https://www.who.int/blueprint/priority-diseases/key-action/novel-coronavirus-landscape-ncov.pdf?ua=1

   

https://endpts.com/a-quick-slice-of-the-data-from-a-small-remdesivir-study-suggests-it-may-be-working-against-covid-19-but-all-the-big-questions-remain-to-be-answered/

https://www.the-scientist.com/news-opinion/covid-19-vaccine-frontrunners-67382

https://www.nih.gov/news-events/news-releases/nih-clinical-trial-hydroxychloroquine-potential-therapy-covid-19-begins

https://cepi.net/covid-19/

https://www.nytimes.com/2020/04/12/health/chloroquine-coronavirus-trump.html?auth=login-email&login=email

https://www.acc.org/latest-in-cardiology/articles/2020/04/10/15/06/acc-joins-aha-hrs-in-statement-on-exploratory-covid-19-treatment-drug-interactions-on-qtc