COVID-19 Vaccines Diligence Report

September 21, 2020

Executive Summary

In the midst of a global pandemic, pharmaceutical and biotechnology companies are in a race to develop the first coronavirus vaccine.  Understanding this landscape is key for understanding future market trends and where to invest.  Here, Enventure provides analysis on COVID-19 vaccines, performing diligence on SARS-CoV-2 data and the global response, as well as an assessment of the competitive landscape and market trends.

We provide a comprehensive overview of COVID-19, delving into the latest science surrounding the virus, providing transmission and symptoms information, and detailing current interim treatments being used until a vaccine is approved.  This overview is followed by an assessment of the worldwide pandemic response, identifying countries which may be more at risk and in need of a vaccine.

The report closes with a deep dive into the COVID-19 vaccine market, providing data on key players, vaccine development timelines, and market growth opportunities and restraints.  These components taken together provide a thorough understanding of the market and can help investors to decide both where and when to invest.

COVID-19 Overview

SARS-CoV-2

Coronaviruses are positive-sense RNA viruses with a viral envelope and spike proteins (S), which give a crown-like appearance.1  These viruses are classified by four genera (𝛂, 𝝱, 𝛄, 𝝳) as well as their pathogenic origin (human or zoonotic).2  SARS-CoV-2 is a zoonotic pathogen that has been phylogenetically classified as a 𝝱-coronavirus, belonging to the subgenus Sarbecovirus.2,3  It is most closely related to SARS-CoV-1 found in bats in China (89.1% nucleotide similarity),  providing strong evidence for a potential origin in Chinese bats.3,4  

The first four cases of COVID-19, the disease caused due to SARS-CoV-2 infection, were reported in 2019 in Wuhan, China.  All patients reported working at the Huanan Southern Wholesale Market, in the presence of live poultry, aquatics, and wild animals.5  It is theorized that SARS-CoV-2 mutated from a coronavirus in a wet market animal due to the chaotic environment, which “weakens the animals’ immune systems and creates an environment where viruses from different species can mingle.”6

Since the initial discovery of the virus, more information has been collected about structural properties and strategies for drug targeting.  Its structure was characterized using cryo-electron microscopy, and was found to be very structurally similar to the SARS-1 spike protein.  However, SARS-CoV-2 was found to bind 10x more tightly to host cells.7  The virus specifically targets ACE2 and TMPRSS2 receptors.  TMPRSS2 is a common receptor on cells, while ACE2 is typically present at low levels depending on sex (more common in men), age, and smoking habits.8  Both receptors are primarily expressed in bronchial transient secretory cells, and thus COVID-19 has taken the form of a respiratory disease.9

Transmission 

Mode of SARS-CoV-2 virus transmission for COVID-19 is predominantly airborne — respiratory droplets and aerosols — produced when an infected person coughs, sneezes, or talks.10,11 The respiratory droplets cause short-range virus transmission by settling out of the air and contaminating people or objects. A small part of the virus transmission might be through contaminated surfaces. According to a recent study, only 3% of the tested household objects and 15% of wastewater samples were contaminated.12

Whereas, aerosols cause long-range virus transmission as they disperse in air and spread over long distances and time. Due to this extended reach, social distancing is not sufficient to prevent the spread of the outbreak. Wearing face masks, however, does appear to provide a significant benefit in preventing the spread of infection by limiting aerosol transmission.10 

Interestingly, the SARS-CoV-2 virus can spread from both symptomatic and asymptomatic (or pre-symptomatic) individuals. While viral spread from symptomatic patients can be monitored, the transmission of the virus through asymptomatic people — accounting for 60% of transmission — has been a significant problem in curbing the spread of COVID-19.13  Inhaled virus particles deposits in the upper respiratory tract (nose, sinuses, upper throat) leading to the spread even during talking (unlike coughing, where the viral particles from lungs are dislodged). The elevated amount of viral particles in the upper respiratory tract of patients with no symptoms is unusual in SARS-CoV-2 compared to other coronaviruses.14

Symptoms

COVID-19 affects different people in different ways. Symptoms for COVID-19 manifest in a diverse range from mild to severe illness.15 Symptoms generally appear 2-14 days after the exposure to the virus, with a median time of 4-5 days from exposure to symptom onset.16 Some of the symptoms listed by the Center for disease control and prevention (CDC)17 are:

  • Cough, sore throat
  • Fever or chills
  • Shortness of breath or difficulty breathing
  • Fatigue, muscle or body aches
  • Headache
  • New loss of taste or smell
  • Congestion or runny nose
  • Nausea or vomiting
  • Diarrhea
  • New confusion
  • Bluish lips or face
  • Inability to wake or stay awake

A study with over 44,000 persons with COVID-19 from China showed that SARS-CoV-2 virus can lead to symptoms ranging from mild pneumonia (81%) to severe respiratory failure, septic shock (5%), and death.18 The same study also found that the fatality rate was the highest among older people. Older adults and persons with predisposed medical conditions may exhibit delayed appearance of fever and respiratory symptoms.19

Current Treatments

The following treatments are approved antivirals, antimicrobials, and immune therapies being repurposed to alleviate symptoms of COVID-19 and reduce hospital stay until a vaccine is widely available.20-22 

There are no FDA approved treatments for COVID-19, but several treatments including Remdesivir and convalescent plasma have been given emergency use authorization (EUA) by the FDA.23-24  As of now, corticosteroids such as Dexamethasone are the only therapy proven to improve survival odds for critically ill COVID-19 patients.  The WHO recently issued new guidelines stating that corticosteroids should become the standard of care for those with “severe and critical” COVID-19.25

Worldwide & U.S. Response

Worldwide Response

Successes

Two of the most successful responses to the COVID-19 pandemic come from countries neighboring China, the source of the outbreak. Taiwan (487 cases; 7 deaths) and South Korea (11,902 cases; 276 deaths) had very aggressive responses to the initial outbreak of the virus.26 These countries have experience dealing with outbreaks in the past, most notably SARS and MERS, allowing for efficient and effective measures to be developed even before outbreaks occur. Both South Korea and Taiwan shut down their borders very soon after the first reports of the outbreak to limit the entrance into the respective countries. In addition, these countries used mobile contract tracing to monitor infected individuals and track down anyone else who may have been exposed. This tactic allows the government to prevent any further spread of the virus from infected individuals. There was also an increase in the production of medical supplies in the event of a large outbreak.27

New Zealand (1,504 cases; 22 deaths)26 is another standout for a successful response. Granted the country is geographically isolated, New Zealand still implemented a stringent and effective response. The borders were quickly closed, and a “level 4 lockdown” was imposed, limiting interactions to immediate family members. The government was also very responsive by hosting Facebook live videos and sending frequent text messages to the people of New Zealand.28 The government also instituted many tax reforms to help small businesses to stay open and promised its residents that they would not lose their residence if they lost their job during the outbreak.28

Another exemplary governmental response to the virus was from Canada (98,645 cases; 8,035 deaths).26 Similar to South Korea and Taiwan, Canada has a history with outbreaks spreading from China to its shores, including the SARS outbreak in 2003. The Canadian government has since made preparations so that all hospitals are well equipped to deal with future outbreaks, like COVID-19. The government has also streamlined communication between federal, provincial, and local healthcare officials and workers to allow for seamless flow of information and supplies.29

Failures

One of the hardest hit countries by the pandemic was Brazil (3.72 million cases).26 The country’s high case count is largely attributed to the lack of governmental response to the initial outbreak. The federal government in Brazil did very little to attempt to mitigate the dangers of the outbreak, putting the responsibilities on the individual municipalities to make their own rules, leading to very uneven mandates. In addition to the lack of governmental response, Brazil has a large wealth disparity, which caused huge outbreaks in impoverished areas that lack proper housing and medical care. The country had almost no testing in the early stages of the outbreaks and made very limited attempts at contact tracing.30

India (3.23 million cases)26 is experiencing a similar situation. One of the greatest problems India faces with this outbreak is the incomplete healthcare system. This lack of development means the citizens have very little access to medical supplies and the government made very feeble attempts to thwart the virus from spreading. In addition, India has one of the highest population densities of any country, with large rural populations that travel great distances for work. The general population also has a very low level of concern for the dangers associated with COVID-19, and is therefore unlikely to take the necessary precautions.31


Cumulative cases of COVID-19 by country

The United States, Brazil, and India have the highest case counts. Canada, South Korea, New Zealand and Taiwan have low case counts and are examples of countries that have had a strong response to COVID-19.26

COVID-19 Testing Implementation

Countries with low case counts, such as New Zealand, have high rates of testing. The inverse is also true - countries with high case counts, have very low levels of testing.26

U.S. Response

The United States currently has the highest case count of any country (6.32 million),26 almost double any other country's case count. Although the United States implemented many different economic reforms to support the economic lockdown, the federal government had a late response in taking certain safety measures such as required mask use and preventing large gatherings. 

In terms of state-level success in fighting the virus, there are five criteria which need to be considered when tracking the progress of each state.32-24

  • Sustained two week drop in cases (10% drop in two weeks)
  • Less than 4 new cases per 100,000 people daily new cases
  • More than 150 tests per 100,000 people daily
  • Less than 5% positive rate on tests
  • Less than 60% occupation of ICU beds

As of September 2, only four states have met 4/5 of the criteria. No state has met all criteria for progress in combating the COVID-19 pandemic. 

The pandemic is also likely to have an impact on the upcoming 2020 election. There is likely to be a decrease in voter turnout at public polling locations because of the increased anxiety associated with being in public with large gatherings of people, this is especially true for high-risk groups. This will likely result in an increase in alternative forms of voting (mail-in, absentee).35

Vaccine Industry

Product Overview

Pipeline

Timeline

Comparison of the established process of research and development for an average (normal) vaccine versus the predicted process for a novel SARS-CoV2 vaccine. Notably, a SARS-CoV2 vaccine is predicted to be approved and manufactured several times faster (14-20 months vs 12-20 years) than other vaccines. This unprecedented rate of development will likely result in the fastest vaccine development and approval in history. Cost estimates depend on the success of each stage.36-40

Vaccine Types

There are multiple vaccine types that aim to expose a relatively harmless version or antigen of the virus in order to stimulate an immune response and provide long-term protection for the individual.

Virus vaccines use an inactivated or weakened version of the virus itself.41 A virus is considered inactivated when it loses its infectious capability via chemical or thermal means. Because of these means, large quantities of the infectious form of the virus are needed. A weakened virus is a virus that was mutated after propagating between human and animal cells. Its disease-causing ability gets weaker as a result of these mutations, but it still replicates within cells. As a result, it requires time, effort, and frequent verification to monitor the weakening of the virus. In either version, the virus is taken in by an antigen-presenting cell (APC), which expresses the coronavirus peptide and stimulates immunity. Virus vaccines have been previously used against diseases such as the flu, polio and measles, but they require significant testing to check the safety of administering an attenuated virus.41,42

Viral vector vaccines are created by genetically inserting a gene that can stimulate immunity against the coronavirus into a different viral vector, such as an attenuated measles virus or adenovirus.41 Vaccines that use viral vectors can be further sub-categorized into replicating and non-replicating vectors. The main difference is the ability to replicate within cells in the body. These viral-vector vaccines have a similar mechanism to the virus vaccines in that they get taken in by APCs, and the coronavirus protein is expressed to initiate the immune response. Because the viral vector carrying the inserted coronavirus protein-expressing gene has been studied previously, these vaccines tend to be safer than virus vaccines while leading to strong immune responses. While there are no licensed vaccines that incorporate non-replicating vectors, they have been previously used in gene therapy applications. Replicating viral vectors, however, have been successfully used in making the recently approved Ebola vaccine. One drawback of using replicating viral-vector vaccines is that common vectors could have reduced effectiveness in individuals with existing immunity against them.  This is why researchers have to source a vector that is less likely to be recognized and attacked by the immune system.41,43

Protein-based vaccines incorporate the protein components of the coronavirus, including viral protein subunits or virus-like particles.41 By administering a viral protein subunit such as one that resembles the receptor binding domain of the coronavirus, the APCs can take up the proteins and express them for immune cells to recognize. However, multiple doses and co-administering these protein subunits with adjuvants are possibly needed to ensure effectiveness. Similar to viral protein subunits, virus-like particles such as the outer protein shells of the coronavirus-like structure can be administered because they lack nucleic acids and are not infectious. These types of protein-based vaccines are difficult to manufacture yet effective in eliciting strong immunity. In general, protein-based vaccines are currently being used to protect against hepatitis B and human papillomavirus (HPV) infections.42

Nucleic acid vaccines use DNA or RNA that encode the coronavirus spike protein and once expressed in cells, an immune response is stimulated.41 DNA vaccines introduce the isolated viral DNA into cells via electroporation, which then becomes messenger RNA (mRNA). RNA vaccines on the other hand introduce viral RNA in lipid vesicles, which then aids in cell entry.  In both methods, the viral proteins are produced from the RNA and are taken up by APCs to generate immunity. The main advantages to this vaccine type are its ease of development and its safety in administration, as only the viral nucleic acid is introduced and not the virus itself. However, there are currently no licensed vaccines of this type.41


Specific mechanisms of the four major vaccine types

While there are unique differences among the types, all vaccines will eventually be taken up by the antigen-presenting cell and expressed on its surface in the form of a specific protein marker. The immune cells in the body will recognize this exposed peptide and will generate a specific immune response against it.

Key players characterized by vaccine type

Many leading companies are focusing on developing inactivated virus vaccines and adenovirus viral-vector vaccines due to advantages in development efficiency and proven vaccine efficacy.42,84

Pricing

There are seven vaccines that are currently undergoing Phase III trials:

  1. AstraZeneca/University of Oxford
  2. BioNTech/Fosun Pharma/Pfizer
  3. Sinopharm/Wuhan Institute of Biological Products
  4. Moderna/NIAID
  5. Sinovac
  6. Sinopharm/Beijing Institute of Biological Products
  7. CanSino Biologics

These companies expect to release and distribute a vaccine by the end of 2020 or early 2021.  Vaccines are likely to be offered free to citizens in most of the countries, such as Japan and Russia.44  The Australian government has secured a deal with AstraZeneca and plans to manufacture the vaccine and offer free doses to all citizens.46 Similarly, the U.S government will also pay for the manufacturing and distribution of vaccines to all American citizens.47  However, China is pricing its vaccine at $140 U.S dollars per vaccine.45 

Key Players (U.S.)

Moderna 

Moderna has been a frontrunner in the race for a coronavirus vaccine since entering human trials in March, though the company has never brought a vaccine to market.48,49  The company has secured over $483 million in funding, excluding those received from Operation Warp Speed (OWS).50  Moderna’s candidate, mRNA-1273, is an RNA-based vaccine, a novel type of vaccine that uses mRNA to introduce the desired antigen and trigger an immune response.50-52  Phase II results are positive, showing that patients produce antibodies as a response.42  Phase III trials with 30,000 patients enrolled at UCHealth in Colorado began on July 27.53-56 In late August, Moderna’s experimental COVID 19 vaccine was been tested on 10 adults between the ages of 56 and 70 and 10 elderly adults aged 71 and older.  Thus far, the study has produced promising results, as the vaccine produced neutralizing antibodies that could elicit the immune system.57 However, the lack of minority participation in volunteers could pose obstacles in drug trials and potentially lead to false positive results. Moderna aims to have the vaccine rolled out by Thanksgiving, and has partnered with Lonza to increase its dose manufacturing capabilities to 1 billion annually.58,59

Inovio Pharmaceuticals

Like Moderna, Inovio Pharmaceuticals is a small biotech company who has never brought a vaccine to market, yet shows enough promise to be chosen as an OWS finalist and secure $71 million from the U.S. Department of Defense.60,61  As the company focuses on the discovery and development of synthetic DNA products, naturally their vaccine candidate (INO-4800) is DNA-based.62  Phase I results show that the vaccine is “generally safe and well-tolerated,” and 34/36 participants generated an immune response within 6 weeks of the vaccine being administered.61  Phase II/III trials have begun but the company is currently in a legal battle with a key manufacturing partner that claims Inovio stole its technology and has sued by shareholders on its exaggerated progress on vaccine development to inflate its stock market price.63 Inovio is not on the list of companies selected to receive financial support from the government for mass-production.64

Pfizer | BioNTech

BioNTech, a German biotechnology company, partnered with American-based Pharma giant Pfizer in developing an mRNA vaccine that’s following close behind Moderna’s mRNA-1273.65  BioNTech and Pfizer have received over $250 million in private funding, as well as recognition as a top five finalist in OWS.66,67  While the partners are currently developing four RNA-based vaccines, BNT162b1 is their top vaccine candidate at the moment.68  Phase I/II trial results published on July 1 showed that every volunteer produced antibodies against SARS-CoV-2.69 The vaccine was granted FDA Fast Track Designation in mid-July and is currently in Phase III clinical trials.63,70  The company expects the vaccine to be available by the end of October this year.71

Novavax, Inc.

Novavax, a late stage vaccine development company based in Maryland, is developing a protein subunit vaccine (NVX-CoV2373) based on the coronavirus spike protein (S protein).72,73  The company has not only been chosen to participate in OWS, but has been awarded $1.6 billion in funding from the U.S. government.72  This came as a surprise to many, as the company entered clinical trials in May, relatively late compared to competitors.  Phase I clinical trials have shown promising results and the vaccine has been undergoing Phase II clinical trials since August.74

Johnson & Johnson

Through its Janssen Pharmaceuticals division, J&J is developing an adenovirus vaccine (Ad26.COV2-S) using an engineered version of Ad26, which usually causes the common cold.75,76  Despite being chosen as a finalist in OWS, the vaccine was in the preclinical stage for much longer than many competitors.77  The vaccine began clinical trials in July in the U.S. and Europe.78  The company claims the vaccine could be ready for emergency use in early 2021, and is still determined to follow through on their goal of providing over 1 billion doses by the end of 2021.79

Key Players (Global)

AstraZeneca | University of Oxford

Despite its late entrance to the race, the University of Oxford’s vaccine candidate has experienced quick success. ChAdOx1 (AZD1222) is a weakened non-replicating adenoviral vector fused with the spike protein DNA, which prompts the body to mount an immune response and develop antibodies against SARS-CoV-2.42,80  AstraZeneca joined forces with the University in April, after Phase I clinical trials.81  Their promising results have resulted in being chosen as a finalist in the U.S. Operation Warp Speed, securing $1.2 billion in funding from the U.S. government alone.81  The partnership has additionally afforded a multitude of collaborations and partnerships (U.K. Government, WHO, Coalition for Epidemic Preparedness Innovations, Gavi the Vaccine Alliance, and the Serum Institute of India) which have increased its potential global manufacturing capacity to 2 billion doses.82  The vaccine entered Phase III clinical trials in Brazil in June and in the U.S. in August.83,84 Once approved, the company is prepared to manufacture 3 billion doses.85 However, the company recently experienced a minor setback in early September - Phase III clinical trials have been paused due to rare neurological adverse side effects observed in one UK patient.86  Investigations are ongoing, so the viability of this key leader is temporarily unknown for the time-being.

Wuhan Institute of Biological Products 

Under the Chinese National Biotec Group (CNBG), the Wuhan Institute of Biological Products is developing an inactivated vaccine.42  This inactivated vaccine was the first of its kind to enter clinical trials in China, and third to enter clinical trials overall.87  Results from the Phase I/II study boast antibody development in 100% of volunteering participants.88  In late June, CNBG agreed to begin Phase III clinical trials in the United Arab Emirates for both of its inactivated vaccine candidates (See 2.3a below).89  The vaccine is currently undergoing Phase III clinical trials and the company aims to release the vaccine by December this year with a price of approximately $140 per vaccine.45

Beijing Institute of Biological Products

Similar to the Wuhan Institute of Biological Products (WIBP), the Beijing Institute of Biological Products is developing an inactivated vaccine under CNBG.42  This inactivated vaccine followed WIBP’s candidate, and was fourth to enter clinical trials in China.90 Phase I/II clinical trial results show that the vaccine is safe and able to produce high titers of antibodies in participants.91 As referenced above, the vaccine entered Phase III clinical trials with its sister vaccine on June 23 in the United Arab Emirates.89

Sinovac

Sinovac, a biopharmaceutical company based in China, is developing CoronaVac.42,92  This inactivated vaccine is the third of its kind in late-stage clinical trials in China.93  Results from Phase II clinical trials showed an absence of severe side effects and successfully triggered an immune response in above 90% of participants.42,94  The vaccine candidate entered Phase III clinical trials on July 6 in Brazil.95  The company is hopeful that the trial could take as little as three months, positioning them to be ready to enter the market in the late September, early October timeframe.96 The company is one of few currently in Phase III trials, and definitely one to watch.

CanSino Biologics | Institute of Medical Biology | Chinese Academy of Medical Sciences

CanSino Biologics is currently developing AD5-NCOV, a non-replicating viral vector (adenovirus) vaccine that has been a long-time leader in the global race for a coronavirus vaccine.97  It was the first in the world to enter clinical trials in March, and quickly entered phase II only a month later.97,98 The vaccine was also recently approved for emergency medical use for the Chinese military on June 25.97,98 Despite its early successes, the company has only began Phase III clinical trials in late August.99

Gamaleya Research Institute of Epidemiology and Microbiology in Moscow 

On August 11, Russia became the first country to approve a coronavirus vaccine for widespread use, despite its failure to complete Phase III clinical trials. The vaccine is made of two adenoviruses, Ad26, which is similar to the developed by Johnson & Johnson, and a booster Ad5, which is similar to the one developed  by CanSino Biologics. Although the vaccine has been condemned by scientists around the world, it will be begin to be distributed to healthcare workers and teachers in Russia.100

U.S. COVID-19 Vaccine Leaders

Leaders chosen due to most advanced stages in development and/or recognition as a finalist in U.S. Operation Warp Speed.42,48-79,84

Global COVID-19 Vaccine Leaders

Leaders chosen and ranked according to the most advanced stage in development.42,80-100


Industry Outlook

The current global vaccine market is estimated to bring in $59 billion in revenues in 2020, and is expected to grow with a compound annual growth rate (CAGR) of 5.2%-8.7% between 2020-2027.101 This growth would bring revenues to approximately $81 billion in 2027. Currently, the global market share is dominated by 4 main players (GlaxoSmithKline, Sanofi, Merck, Pfizer), comprising 85% of the total market. The United States currently makes up 30% of the global market share. 

The global COVID-19 vaccine market is expected to be worth $2.3 billion by 2022.102 Assuming a $70 billion vaccine market size in 2022, COVID-19 vaccines would account for about 3% of the total vaccine market. The estimated CAGR from 2022-2025 for the COVID-19 vaccine market is -14.9%, leading to a market size of around $1.4 billion in 2025. Globally, the highest CAGR is predicted to take place in the Asia-Pacific region, 

due to rising populations, growing case counts, and early clinical trial approvals.103 

Opportunities 

Government Funding

Operation Warp Speed (OWS) is a public-private partnership initiated by the US government to accelerate the development, manufacturing, and distribution of the COVID-19 vaccine. OWS intends to deliver 300 million doses of vaccine by January 2021.104   

To accelerate vaccine development, OWS is investing in multiple vaccine leads simultaneously instead of the traditional sequential fashion.  This increased financial burden is carried by the government to incentivize vaccine development by the private sector. In return, the government will have a share of the successful vaccine from the manufacturer to distribute to the public at affordable costs. 

Congress directed OWS budget of almost $10 billion through supplemental funding (including the CARES Act), of which $6.5 billion is designated for vaccine (and other therapeutics) development through BARDA and $3 billion for NIH research.105 

So far, OWS has invested $1.6 billion in Novavax Inc., $456 million in Johnson & Johnson, $483 million in Moderna, and $1.2 billion in AstraZeneca’s vaccine candidates. OWS also funded $450 million to Regeneron to help produce an antibody cocktail as a possible therapeutic for COVID-19.77 

Apart from investments for vaccine and therapeutic development, OWS has also invested $628 million to support Emergent BioSolutions’ effort to increase vaccine manufacturing capacity in the US for a potential COVID-19 vaccine.

Besides, the OWS is parallelly building the necessary infrastructure and sourcing raw materials for vaccine distribution in the form of cold storage facilities, glass vials, and prefilled syringes.  This financial investment includes a $138 million contract with ApiJect for more than 100 million prefilled syringes, $204 million to Corning for expanding glass vial manufacturing capacity, and $143 million to Sio2 Material science for glass-coated plastic containers. 

Operation Warp Speed (OWS) fund allocation to vaccine R&D and distribution efforts

Congress directed OWS budget of almost $10 billion through supplemental funding, of which $6.5 billion is designated for vaccine (and other therapeutics) development through BARDA and $3 billion for NIH research. Source: US Department of Health & Human services105

Potential for Mandated Vaccination

The United States federal government will not make the vaccine mandatory for the general public (excluding healthcare workers), according to Dr. Anthony Fauci.106  However, some groups, such as children or students, could be mandated by state or local jurisdiction.  Canada is taking a similar approach, and will just “strongly recommend” that its citizens receive the vaccination.107

Other countries are opting for an obligatory immunization. Australia’s Prime Minister announced that vaccines would be mandatory for everyone in the country (with some medical exemptions), once approved.106  However, he has since backtracked on these initial statements, leaving vaccination requirements for both Australians and travelers more ambiguous.108

Insurance Involvement

Despite the fact that the vaccine will not be made mandatory for the general public, the United States government expects all insurers to cover vaccines for COVID-19 without charging copays.109  In theory, it is financially favorable for insurance companies to cover the price of a vaccine - as it will prevent the potential for much higher charges for COVID-19 treatment and hospital care.

However, under the Families First Coronavirus Response Act, insurers were also expected to cover COVID-19 testing for all Americans - even those who are uninsured, with the caveat that the individual must be deemed “medically appropriate” by the insurer.110,111  If insurers decide to find similar loopholes when a vaccine is approved by the FDA, some Americans could be facing a similar challenge of paying out-of-pocket, with up to $20 a dose.112 

Evolving Strains 

Because SARS-CoV-2 is an RNA virus, it is highly susceptible to mutations.  RNA viruses are known to have exceptionally high mutation rates due to higher rates of replication errors.113  Not all mutations will be advantageous, but it is clear that several mutations have been, due to the increasing number of strains found.  One such strain (G614), found in the US and Europe, has a mutated S “spike” protein that is better able to bind ACE2 receptors.114  This strain is 10x as transmissible as the original strain found in China (D614).  While no evidence has found that the mutation has increased the deadliness of the virus, the contagiousness of the virus has significantly increased.  As of August, there have been at least six strains of the virus identified, but the virus has shown relatively little variability overall.115  In addition, its mutation rate is surprisingly much lower than other infectious diseases, at only half of the influenza mutation rate, for example.116,117  Evolving strains may create potential for growth in the coronavirus vaccine market in the coming years - as several different vaccines may be needed to provide immunity in the future - although the low mutation rate and lack of current variability suggests this is relatively unlikely.

Re-infection

The idea of SARS-CoV-2 re-infection has been a long-time debate throughout the pandemic.  However, recent studies show that antibodies might only circulate for about 2-4 months post-infection for those with mild symptoms, which describe a majority of patients.118,119 In late August, a man in Hong Kong was found to be re-infected with a different strain, just several months after recovering from his first infection.120  On a physician information sharing site called Sermo, 13% of doctors believed they treated a re-infected patient.120  

While it’s still not completely clear whether or not re-infected patients had actually cleared the virus, these findings provide evidence that there is a potential likelihood of becoming re-infected.  Re-infections would greatly increase the size of the COVID-19 vaccine market, as immunizations would be needed at semi-regular intervals to allow individuals to maintain immunity.

Dosage 

It appears that for the vaccines currently in development, more than one dose will be required to create an acceptable level of immunity, according to Bill Gates.121  Moderna, for example, has already anticipated needing two doses, a month apart for their vaccine.  With this assumption, an estimated 7 billion doses would need to be administered worldwide to obtain herd immunity.  The increased number of required doses effectively doubles the initial market size estimations with the assumption of only one dose.

Efficacy and Success Rate

In June, the FDA released guidelines for the approval of COVID-19 vaccines.122  Vaccines must have an efficacy of 50%, meaning those who are vaccinated should have a 50% less likely chance of infection.  Experts have differing views on this requirement.  Peter Hotez, a vaccine expert from Baylor College of Medicine, claims that this number is much too low and that vaccines should be 70-75% effective.  Stephen Ostroff, a former acting FDA commissioner, claims that this number is too high considering the pandemic’s wide ranging global effects.123

There’s currently no data on the length of effectiveness - the first individuals were vaccinated in March, so the durability of the vaccine is yet to be determined.124  Developers are hopeful that the vaccine will last for at least a year before boosters are needed.  It’s also worth noting that a vaccine will potentially only prevent severe disease, and so mild disease could still be a potential effect.

If initial vaccines aim for minimal required efficacy, it’s probable that the market will continue to grow as research efforts are allocated toward improving approved vaccines. 

Restraints 

Vaccine Adoption Issues

One of the major restraints for the growth of the coronavirus vaccine market is the willingness of citizens to receive the vaccination.  Several surveys across countries around the world have shown differing results as to how many people are willing to be vaccinated against COVID-19.  

In the United States a Gallup poll was recently conducted in August, asking respondents whether or not they would be willing to receive an FDA approved vaccine at no cost.125  65% of respondents stated that they would be willing to be vaccinated, while 35% said they would not.  NBC News conducted a similar poll and found that 44% of Americans would be willing, 32% were unsure, and 22% would refuse to receive vaccination.126  Though these numbers seem surprising at first, Americans have historically reported similar attitudes toward vaccination, such as in the 1954 poll regarding the polio vaccine where only 60% of respondents said they would be willing to be vaccinated.  

The attitude toward COVID-19 vaccination appears to be much different in Europe, where 73.9% of respondents stated that they would be willing, 18.9% stated they were unsure, and only 7.2% said they do not want to be vaccinated.127  Of those who responded they were unsure, a vast majority (70%) were hesitant because of potential side effects and safety concerns.  Similarly, 50% of those who said they did not want to be vaccinated had the same reasons for their response. 


American and European public feelings toward COVID-19 vaccination

Survey results indicate that American citizens are much more hesitant to receive a COVID-19 vaccine than Europeans.  A majority of Americans are either unsure or do not want to receive a vaccine, even if offered for free.126,127

Based on initial survey results, it appears that there is a larger market in Europe due to higher consumer demand (higher percentage of willing participants coupled with a larger population).  In addition, it appears that the main reason for the hesitance or unwillingness to receive a coronavirus vaccine is due to concerns about safety and potential side effects.  It will be interesting to compare survey results in several months from now when more data is available from clinical trials and initial rollouts for mandatory groups.

Inefficiencies in Distribution

The limits on vaccine manufacturing capabilities require that a system be developed for mass distribution.  In the United States, a federal plan for distribution has not yet been developed, though it will likely be distributed to individual states based on population or epidemiological data.128  Once released to the states, each state will need to develop a plan for local distribution.  The National Governors Association (NGA) has released a policy plan for vaccine distribution in the United States, organizing individuals into five tiers.129

Tier 1 - High Risk I / Essential Healthcare Workers

  • Pregnant women
  • Infants and toddlers
  • Deployed personnel
  • Public health personnel
  • Critical healthcare
  • Pharmacists and pharmacy technicians
  • EMS, law enforcement and file services
  • Pandemic vaccine and antiviral drug manufacturers

Tier 2 - High Risk II / Essential Workers

  • Household contacts of infants (<6 mos.)
  • High risk children
  • Essential military support personnel 
  • National Guard
  • Intelligence services
  • Other domestic national security
  • Mortuary services
  • Other health care personnel
  • Community services
  • Communication, IT, and utilities
  • Critical government operational and regulatory personnel

Tier 3 - High Risk III / Other Essential Workers

  • Healthy children
  • Other active duty
  • Other healthcare
  • Other critical infrastructure sectors
  • Other critical government

Tier 4 - High Risk IV

  • High risk adults
  • Adults ≥ 65 years old

Tier 5 - Healthy Adults

  • Healthy adults (19-64 years old)


Proposed vaccine distribution at the state level

Several governors have drafted a policy outlining tiers of priority for vaccine distribution.  These five tiers prioritize the highest risk populations first and end with the population of healthy adults.129

While more concrete distribution plans are currently in development in the US, less affluent countries are struggling to pre-order vaccines.  The U.S. has ordered 800 million doses from at least six vaccines in development with a potential purchase of an extra billion doses, the U.K. has ordered 340 million doses (highest per capita buyer at about 5 doses per citizen), and the E.U. and Japan have also claimed hundreds of millions of doses.130  Thus vaccine nationalism has already arisen, creating a significant obstacle for equitable global vaccine distribution.  An international coalition fund (COVAX) is trying to secure 2 billion doses, where half will go to 92 low- and middle-income countries (who will pay little to nothing) and the other half will be allocated for 75 wealthier countries (who will fully pay for the vaccines).  So far, COVAX has only secured 300 million doses due to lack of funds required to scale up vaccine production and delivery.130  Manufacturing and funding limits will create distribution restraints not only within countries, but also globally across countries.

Herd Immunity

As COVID-19 cases rise, more and more people worldwide will have antibodies and passive immunity against the virus, and will be less likely to request or receive the vaccine.100-101 Thus, the sooner a COVID-19 vaccine is commercially available, the larger its worldwide market will be.  However, as of September, only 1.9% of the US population has been infected with SARS-CoV-2 over the course of 2020.32  Considering that 60-70% of the population would need to have developed antibodies against the virus to attain herd immunity, it seems unlikely that the market size will significantly decrease with the rising number of cases, assuming similar infection rates and that a vaccine is approved by the FDA within the next year.131

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