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Not since the Swine Flu epidemic of 2009 has there been this amount of emphasis on vaccines and vaccine development.  This new infectious disease threat with no anti-viral, nor vaccine is causing significant concern among healthcare providers, governments and the public.  Last-resort measures such as school closings and curfews in place in the United States has only increased focus on a vaccine solution that could provide enough protections to individuals.

Kalorama covers vaccines markets from 2018 to projected 2024 markets in its market research study: https://kaloramainformation.com/product/vaccines-2018-world-market-analysis-key-players-trends-pediatric-and-adult-segments-influenza-cervical-cancer-combinations-hepatitis-pneumococcal-mmr-varicella-poliovirus-hib-others/
A new report will be out in July 2020.

Some diseases have proven extremely difficult to address through vaccines – HIV, for example. However, although much is unknown about COVID-19, it is nonetheless a respiratory disease that belongs to a class of diseases – corona viruses – that is well understood.  This provides more confidence

We talked with our vaccine analysts to get their sense of the landscape with novel coronavirus.

Early Efforts and a First Trial Dose

COVID-19 vaccine candidates are now heading into trials. Companies in various stages of development include Gilead, GlaxoSmithKline, Pfizer, Moderna, Medicago and others.

Pfizer chairman and CEO Dr Albert Bourla said: “Many companies, including Pfizer, are working to develop antiviral therapies to help infected patients fight this emerging virus as well as new vaccines…Pfizer is working to advance our own potential antiviral therapies and is engaged with BioNTech on a potential mRNA coronavirus vaccine.”

Cambridge, MA-based Moderna announced first participant dose in a Phase 1 trial for mRNA-1273 against the novel coronavirus.  Moderna’s mRNA-1273 is an mRNA vaccine against SARS-CoV-2 encoding for a prefusion stabilized form of the Spike (S) protein. The company’s Phase 1 study is evaluating the safety and immunogenicity of three dose levels of mRNA-1273 (25, 100, 250 μg) administered on a two-dose vaccination schedule, given 28 days apart. A total of 45 healthy adults will be enrolled in the study. Participants will be followed through 12 months after the second vaccination. The primary objective is to evaluate the safety and reactogenicity of a two-dose vaccination schedule of mRNA-1273. The secondary objective is to evaluate the immunogenicity to the SARS-CoV-2 S protein.

This is a major opportunity for vaccine developers, so it is likely that if a developer has a vaccine  that could be even partially effective, they will do everything possible to move it thru trials quickly.   At the same time, governments are looking for more tools to contain the spread. It’s clear that steps taken to date have not been sufficient.   So they are highly motivated to support vaccine development efforts.

Technology 

Demand is not the issue, according to Kalorama’s vaccine analysts.  The market pull will be there, but in vaccine markets, where customers are generally governments, it comes down to the technology – the products.

Some diseases have proven extremely difficult to address through vaccines – HIV, for example. However, although much is unknown about COVID-19, it is nonetheless a respiratory disease that belongs to a class of diseases – corona viruses – that is well understood.  This provides more confidence that it is possible to create a vaccine that would protect some portion of the population.

Since other countries do have significant vaccine development resources – China, India, Japan, etc. – it is certainly possible that a vaccine could be developed overseas before one is developed in the U.S. In fact, I would guess that Chinese vaccine developers began working on this weeks before U.S. vaccine developers.

The Gaurdian reported that about 35 companies and academic institutions are racing to create such a vaccine, at least four of which already have candidates they have been testing in animals.

Stat News reported about an interesting synthetic mRNA solution that is being developed.   https://www.statnews.com/2020/03/11/researchers-rush-to-start-moderna-coronavirus-vaccine-trial-without-usual-animal-testing/ that would be “programmed with the goal of getting our inner machinery to produce certain coronavirus-like proteins — the very proteins that the pathogen uses to gain entry into our cells. Researchers at Moderna and the NIH think that once those homemade dummy virus particles are there, the thinking goes, our bodies will learn to recognize and clobber the real thing.”

Production

Of course, developing a vaccine is only part of the problem. Any vaccine would have to be effectively manufactured and distributed. That could create significant roles for many other players.

Most inactivated influenza vaccines are produced by growing influenza viruses in eggs.  This requires a staggering amount of them. For the H1N1 flu vaccine, a million eggs are required for 3 million doses, more or less.

Egg-based production process begins with candidate vaccine viruses (CVVs) grown in eggs provided by the CDC or approved partner per current FDA regulatory requirements. These CVVs are then injected into fertilized hen’s eggs and incubated for several days to allow the viruses to replicate. The fluid containing virus is harvested from the eggs.

Cell-based flu vaccine has been developed as an alternative to the egg-based manufacturing process. On August 31, 2016, FDA issued an approval for Seqirus, the sole FDA-approved cell-based flu vaccine manufacturer in the United States, to begin using cell-grown CVVs.  Cell culture technology is potentially more flexible than the traditional technology, which relies upon adequate supply of eggs. Recombinant DNA manufacturing is another option. This method does not require an egg-grown vaccine virus and does not use chicken eggs at all in the production process. Instead, manufacturers isolate a certain protein from a flu virus. This proteins are then combined with portions of another virus that grows well in insect cells and allowed to replicate. A protein is harvested from this mix that is used to make the vaccine.

According to a recent article in the Los Angeles times, there are many different vaccine-making platforms, each with its own set of advantages and disadvantages. https://www.latimes.com/science/story/2020-03-12/why-does-it-take-so-long-to-make-a-coronavirus-vaccine “For example, a vaccine based on the virus’ genome can be made quickly, in perhaps a month or two, but it may be harder to manufacture in giant quantities. Another option is to take the virus’ genetic snapshot and put it into a different virus for transport. These vaccines take longer to make — say, six to eight months — but they can be scaled up more readily.”

” almost 33% of readers believe it will take over a year, while slightly more 28% are optimistic there could be a vaccine available within three months.” -Pharmaceutical Technology

An article in Pharmaceutical Technology  said that “Readers of Pharmaceutical Technology have been voting on how long they think it will take for a vaccine to be available to patients. With over 164,000 votes cast, the results show than almost 33% of readers believe it will take over a year, while slightly more 28% are optimistic there could be a vaccine available within three months.”

In general,  this is a very major opportunity for the vaccine industry to shine.  We would expect it to rise to the occasion with at least one, if not several, potential products.  Kalorama will of course report on updates in our biennial vaccine market research study.

 

coronavirus

The House of Representatives and Senate today passed an $8.3 billion spending package to help providers and local governments handle the spread of the coronavirus and to boost the development of vaccines and tests of the virus.  While vaccine support and spending on healthcare is expected, the bill also  boosts telehealth solutions with financial support and positive regulatory changes. 

Telehealth, or as Kalorama defines it, remote patient monitoring, is a $42-billion dollar market

The coronavirus response bill released by Congress on March 5th expands the Medicare reimbursement for  providers using who treat patients via telehealth to treat seniors at home.  The emergency spending bill waives Medicare’s geographical restrictions on telehealth during a public health emergency, enabling providers to use telehealth in both urban and rural areas as well as in the patient’s home as part of an “emergency area.”  Previously this was limited to rural areas.  It also loosens definition on telehealth devices, essentially allowing any device connecting physician and patient with audio and video capabilities.  This is a significant boost for telehealth and is understandable given the spread of the disease and the need to both service patients and protect physicians, nurses and other staff.

Most importantly, the bill contains mandatory funding authorization for $500 million over 10 years to be used toward a remote health care program.

This is a boost for the patient monitoring and telehealth market.  Kalorama Covers Remote Patient Monitoring in This Report: https://kaloramainformation.com/boost-for-42-billion-dollar-remote-patient-monitoring-market-in-covid-19-bill/

The global patient monitoring and telehealth market is estimated to be worth about $42 billion in 2019, inclusive of devices, peripherals, software, packaged services, monitoring services and other applications.  The market has benefited from the demand to move to a more wireless and streamline operation both within major health facilities and in-home treatment markets.  The demand to integrate data processing capabilities and EMR transfer options has also fueled the market.  There is also an increasing trend to upgrade to ambulatory and hand-held devices.

No longer is telehealth for rural patients alone.  For qualified providers, an emergency waiver will allow telehealth to be reimbursed by Medicare.   And extra funding is provided.

The interest in telemedicine and telehealth has exploded over the last decade.  Involvement in this care segment has several benefits and hospitals, caregivers, device manufacturers, and patients are continuing to jump on board with acceptance using this technology.  There are more than 700 clinical trials using telehealth recently completed, currently underway.  The global patient monitoring and telehealth market has continued its expansion in both the institutional and home segments of the health market with the United States and many European countries at the forefront of implementation.

 The industry spoke in the past few days and Congress listened.  In a recent letter sent to Senate Majority Leader Mitch McConnell, R-Kentucky, House Speaker Nancy Pelosi, D-California, and other Congressional leaders, the ATA – along with HIMSS, the eHealth Initiative, Health Innovation Alliance and Personal Connected Health Alliance – has asked Congress to make money from the COVID-19 supplemental appropriation available for more telehealth services.

Unique Opportunities in Telehealth/Telemedicine

There are a number of market opportunities in telemedicine that may offer some benefits over traditional office-based care.

For example, AMD Telemedicine’s General Exam Camera and Telephonic Stethoscope were used in a pilot program to treat Illinois inmates with HIV and Hepatitis.   Other examples include using telehealth to address the growing need for mental health monitoring and intervention.  This is an area where interest has increased significantly, as barriers to treatment are three-fold: lack of treatment resources; lack of adequate medical coverage; embarrassment.

Mental Health Assessment through Telemedicine

Telemedicine in the area of mental health disorders and conditions is often referred to as telemental health or telepsychiatry.

One area of mental health therapy is PTSD a type of anxiety disorder brought on by very traumatic situations such as war.

The costs of PTSD are difficult to accurately pinpoint because it may manifest itself in different ways for different people. Some patients seek therapy in unhealthy methods such as through alcohol and drugs. Lost wages, mortality, therapy sessions, physical health problems (non-psychiatric care), and prescription drugs are all costs associated with treating PTSD.

Caregivers may use telepsychiatry when they move or if the patient moves. Telehealth has the potential to increase the time a patient can see one caregiver, which has been linked to improved care, and can be beneficial for the worker who can keep some of their income after a move, even if it is only on a part-time basis.

Currently, in traditional fee-for-service Medicare, use of the telehealth benefit is limited to rural Health Professional Shortage Areas (HPSA1), CMS defined telehealth originating sites, and synchronous telehealth services. The Next Generation ACO Telehealth Expansion Wavier eliminates the rural geographic component of originating site requirements, allows the originating site to include a beneficiary’s home, and for the use of asynchronous telehealth services in the

specialties of teledermatology and teleophthalmology.

The waiver will apply only to beneficiaries aligned to a Next Generation ACO and for services furnished by a Next Generation Participant or Preferred Provider approved to use the waiver.  An aligned beneficiary will be eligible for the Telehealth Expansion Waiver if the beneficiary is located at their home or one of the Centers for Medicare & Medicaid Services (CMS) defined telehealth originating sites.

Medicare currently covers a limited number of Part B services delivered by an approved provider to a Medicare beneficiary. The beneficiary must be located in an approved “originating site” and services must be delivered by face-to-face consult using live video conferencing technology.   Originating site under existing Medicare telehealth rules include.

– Physicians’ or practitioners’ offices

– Hospitals

– Clinics and federally qualified health centers

– Hospital-based renal dialysis centers (including satellites)2

– Skilled nursing facilities (SNFs)

– Community mental health centers

There are a huge number of companies offering some form of wireless and remote technologies, patient data processing applications and equipment, and EMR data transfer equipment.  Competitors supplying patient monitoring and telehealth systems to hospitals are large, established healthcare companies, often working in conjunction with information technology (IT) companies on an entire system.  The home healthcare and other sectors are much more fragmented and are dominated by privately held companies.  In addition, some companies supply innovative products, but only for a small segment of the market; and some companies supply products on a regional basis only.

Although there are many participants in the market, a handful of companies continue to make a significant impact on the patient monitoring and telehealth technologies market.  The top five contributors to the market include:

  • Medtronic
  • Abbott Laboratories
  • Philips Medical
  • Boston Scientific
  • GE Healthcare

With the world’s major health organization upping the mortality rate to 3.4%, there is increased need for a working rapid test for COVID-19 to be able to properly isolate patients and protect providers.

The World Health Organization (WHO) has raised its estimate of the mortality rate of patients infected with the novel coronavirus to 3.4% globally, up from a 2.3% death rate in previous estimates.  In a press briefing in Geneva, WHO Director-General Dr. Tedros Adhanom Ghebreyesus told reporters of the higher mortality estimate based on reports coming in from around the world, according to an article on CNBC.com.

The novel coronavirus SARS-CoV-2 causes the disease COVID-19. As of March 4, 92,943 cases of COVID-19 had been reported globally, with 3,160 deaths, Ghebreyesus noted during a mission briefing on March 4. The WHO has shipped nearly half a million sets of personal protective equipment to 27 countries and has sent “hundreds of thousands of lab tests” to countries in call regions, he said.

The higher mortality estimate for COVID-19 represents a significant escalation of the health risk posed in the event that coronavirus infections spread significantly. Concern about the coronavirus outbreak has already resulted in the cancellation or postponement of public events scheduled for March, such as the European Congress of Radiology in Vienna and the Acute Cardiovascular Care conference in Athens.

By point of comparison, the mortality rate from the seasonal influenza virus is around 0.1% in the U.S., according to published sources.

In the press briefing, WHO officials said that much of the difficulty in estimating the health impact of the novel coronavirus comes from the fact that the virus behaves differently from the flu virus, and the mechanisms by which it is transmitted aren’t fully understood, according to the CNBC report.

On the positive side, they said that in countries with “strong measures” to contain outbreaks, virus transmission can be suppressed.

Please sign up to our sister publication, www.labpulse.com for more information on this disease.

Adding a fifth “vital sign” — that is, travel history — to patient intake evaluations could go a long way toward identifying those at risk of the COVID-19 coronavirus disease and potentially slow its spread, according to a commentary published March 2 in the Annals of Internal Medicine.

A typical patient evaluation includes an assessment of temperature, heart rate, respiratory rate, and blood pressure. But in the context of COVID-19, adding travel history is key, wrote a research pair led by Dr. Trish Perl, chief of the division of infectious diseases at the University of Texas Southwestern Medical Center.

“A simple, targeted travel history can help us put symptoms of infection in context and trigger more detailed history, appropriate testing, and rapid implementation of protective measures,” explained Perl and colleague Dr. Connie Price, a professor of medicine/infectious disease at the University of Colorado.

The clinical community’s experience in dealing with severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and Ebola point to how critical it can be to identify disease through travel history, Perl and Price noted. They cited a missed opportunity in a 2014 Ebola case.

“In Dallas, a patient presented to an emergency department in 2014 after returning from Liberia with low grade fever, abdominal pain, dizziness, nausea and headache,” the authors wrote. “The patient had Ebola. Because clinicians did not obtain the one potentially distinguishing clinical clue — a travel history — the well-being of both the patient and caregivers were compromised.”

In the face of the COVID-19 epidemic, health organizations and individual countries have attempted to control the spread of the virus via strategies such as travel and public gathering restrictions, school closures, and city quarantines, Perl and Price noted. But these measures may not be enough.

“Investigators estimated that there were almost 59,000 cases in Wuhan and 3,500 in other regions in China before the travel ban was implemented. … A recent report suggests that, because of the incubation period for COVID-19, the spectrum of symptoms, and the time during the incubation period persons may fly, 46% would be missed by airport-based screening,” they wrote. “Available data specific to COVID-19 suggest that screening and restricting travelers may have limited impact on containment.”

All members of the healthcare team need to integrate epidemiologic information such as travel history in their risk assessments in the same way they ask about tobacco exposure to assess cancer and heart disease risk, according to Perl and Price.

“They need a simple script to elicit clues for emerging infectious diseases and must be informed about current emerging pathogen threats, such as COVID-19,” the authors concluded. “Including travel history as a vital sign could serve as a warning sign that prompts protective measures.”

Stronger Than Average Threat,  Genetics Reveal 

The rise of next-generation sequencing has led to a boom of viral sequence discovery. The genus betacoronavirus is divided into four lineages (A-D) and contains a number of human viruses. Lineage B has around 200 published virus sequences and includes the severe acute respiratory syndrome coronavirus (SARS-CoV) and the newly emerging SARS-CoV-2 (previously called 2019-nCoV). It is still unknown if other viruses in this lineage have the potential to emerge in humans. Moreover, current techniques to study whether these viruses can enter human cells are technically demanding, time-consuming, and expensive.

Many viruses, including betacoronaviruses, use cell entry as a means of cross-species transmission. All coronaviruses encode a surface glycoprotein — a spike — that binds to the host-cell receptor and mediates viral entry. The host receptor for SARS-CoV-2 has been identified as angiotensin-converting enzyme 2 (ACE2). For betacoronaviruses, a single region on the spike called the receptor-binding domain (RBD) mediates this binding interaction. After binding, the host proteases cleave the spike, facilitating virus entry.

With underlying mechanisms in mind, and with the goal of overcoming testing limitations, Michael Letko, PhD, and colleagues from the NIH took a reductionist approach to studying coronavirus entry. They developed a scalable, biosafety level 2-compatible method for detecting the minimal region of coronavirus that’s essential for interacting with a host receptor.

Relying on the principle that RBDs on coronavirus spikes are capable of folding independent of the rest of the spike protein, and that they contain all of the information needed for host receptor binding, the NIH researchers tested receptor usage of all published unique RBD sequences for lineage B coronaviruses.

They found that lineage B RBDs divide into three functionally distinct clades. Only clade 1 RBDs contain all 14 residues that have been shown through crystallography to interact with human ACE2. Using synthetic biology and molecular engineering, combinations of coronaviruses were generated to test the specificity of RBDs, the importance of protease in viral entry, and whether these two processes are coupled.

The studies revealed that protease-mediated entry is receptor dependent, with ACE2 entry being lineage B clade 1 specific. However, when the spike was genetically modified in clade 2 and 3 viruses, viral entry was improved to varying degrees. This suggests that the limiting factor of viral transmission may be protease processing.

Interestingly, the RBD for SARS-CoV-2 has residues and motifs found in all three clades but uses ACE2. This may explain the human-to-human transmissibility of the virus. It contains most of the contact points with human ACE2 that are found in clade 1 and some amino acid variations that are unique to clades 2 and 3. The researchers suggest that it may be possible that SARS-CoV-2 arose from recombination between clade 1 and the other clades.

Overall, the results of the study emphasize the importance of continued surveillance of coronaviruses at the sequence and functional levels in order to better prepare for the next emerging virus.

A Harvard Business Review  article calls for molecular point of care to step in to detect #coronavirus. You’ll hear a lot of this in coming weeks, we think.  Molecular point of care is less than 10 years old but has shown promise in flu/strep, other respiratory pathogens. They are in the right place at the right time, the clinic, the CVS, they are in parts of the hospital away from the lab.

Kalorama has reports on molecular POC here .  We are in the process of updating the report too, for mid March, to encompass 2019 and early 2020 results.  Placements in clinics make mPOC a good first responder if a test can be developed and systems adjusted.  A big if, but test makers, Cepheid is one, are on the case. https://lnkd.in/ew-TsJq

The more modular the POC system the better, that is to say the coronavirus test should be a cartridge rather than require a new instrument.  Such a test would be in demand right now and with the federal government motivated, EUAs are certainly possible to get around the normal regulatory hurdles.

But it’s not just about a regulator saying yes – a test would have to be high percentages of specificity – a poor test would just add false positives and will swell caseload numbers and increase fear. https://lnkd.in/eP9C98K