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7/14/2022

SARS-CoV-2: Tougher Variants, New Vaccines, Extended Coverage, Slower Vaccine Rates

Tougher Variants: The arrival of further Omicron variants BA.4 and BA.5 have resulted in another surge of global infections
The true extent of the surge is hard to quantify, as there are less testing facilities available, and less interest on the part of the public in testing
- Epidemiologists consider BA.5 - also referred to as the ‘Ninja’ variant - “The worst version of the virus that we’ve seen”, overtaking the ‘Stealth’ BA.2 version of Omicron
- BA.5 is also being referenced as a ‘Deltacron’-like variant, given that is is so transmissible and is showing signs of symptoms in the lungs, vs. other Omicron variants affecting mostly the upper respiratory areas only
- This variant evades immunity from either prior infections or from the initial vaccines in use world-wide over the past 18 months
- BA.5 is causing > 50% of all U.S. infections, based on late June health data
- Infections and hospitalizations in the U.S. have doubled from May to June, but with reductions in reportable testing, some experts think the caseloads could be 10X higher
- Another variant - BA.2.75 - infecting people in India, as the Omicron strain continues to evolve
Estimates on how widespread these new infections are varies from 5%-30% of the population
Hospitalization and death rates as a percentage of infections continue to fall
- This is believed to be driven by the cumulative effect of vaccinations and prior infections, but is not a reduction in the severity of risk in naive (not previously infected/vaccinated) subjects
Vaccination - even with 3 shots of Pfizer or Moderna - has not stopped most infections
Countries with older populations appear to be having worse outcomes (Portugal vs South Africa) irrespective of vaccination status (90% vs. only 50%)
- Good BA.4/BA.5 reference: https://www.nature.com/articles/d41586-022-01730-y
To combat the BA.5 variant, in early July, China instituted a mandatory vaccination program for selected venues - a first of its kind for China - but then quickly scrapped the program after Chinese citizens strongly criticism of the new policy
Meanwhile, given the BA.5 variant, China shut down all gambling casinos in Macau for one week
World Health Organization still considers COVID-19 a global health emergency
Exhibits 1-2 show the extent of the latest surge, in terms of both (probably under-) reported infections, as well as deaths (right-most portions of the exhibits)
- Daily caseloads have almost doubled from 477K in early June to 820K in early July
- Death rates, while down, continue to be non-trivial
- For example, in the United States, current COVID-19 death rates are still running at 3X-4X the annual death rates from motor vehicle accidents
New Vaccines - Annual COVID-19 Shots: Dealing with COVID-19 going forward is - as predicted - beginning to look more like an annual flu shot campaign
The two challenges: 1) Timing and 2) Which variants to target
The risk is that targeted variants will be the wrong targets when the vaccine is ready to go
Pfizer and Moderna have each tested vaccines targeting the initial Omicron strain
- U.S. has ordered 105 Million doses of these new vaccines from Pfizer
The FDA is currently deciding which policy to pursue; signals already being sent to expect new versions of the vaccine to be available this fall
- The independent advisory committee has recommended updating vaccines to include Omicron
- An Alternate Perspective: "Don't Rush a Change to the COVID-19 Vaccine Composition”: https://www.statnews.com/2022/06/29/fda-dont-rush-to-change-covid-19-vaccine-composition/

A large study of long COVID-19 was initiated in the U.S.; it will enroll 40,000 test subjects
Broader Vaccine Coverage, But Declining Vaccine Rates: FDA has now approved Pfizer and Moderna vaccines for children 5 and under
- Controversial Decision - The sickness/death rates in this age group from COVID-19 have been infinitesimal, and unlike nearly all other childhood vaccines, the protection quickly wanes
Global vaccine rates have declined, leveling off between 6-9 Million doses/day - in the U.S., the number is down to 150K doses/day
In many countries with lower vaccination rates, the market has reached saturation due to:
1) Public resistance to vaccination and 2) Feeling by the general public that the Pandemic is ‘over’ and 3) Reduced prioritization of COVID-19 government vaccination campaigns

Vaccine Industry Updates

Valneva: https://pubmed.ncbi.nlm.nih.gov/35718205/, Stage 1/2 test results for its WIV vaccine
- In mid-June Valneva settled with the UK for the the termination of the UK’s Advanced Purchase Agreement (APA) for Valneva’s vaccine
- In late June, Valneva received full marketing authorization for its vaccine in all 28 EC countries and is also now getting country-specific approvals, e.g., Sweden
- Also announced an Equity Subscription Agreement with Pfizer, allowing PFE to invest in 8.1% of Valneva’s shares, participate in the development of a vaccine candidate for Lyme disease
Novavax: 4th vaccine approved in U.S., early June; U.S. ordered 3.2 million doses of this vaccine; will be manufactured by the Serum Institute of India (SII)
- Novavax’s vaccine already available in 40 other countries
- As a protein sub-unit vaccine, the Novavax vaccine is targeted as ‘an alternative to MRNA vaccines’, towards the non-vaccinated ‘vaccine hesitant’ skeptics
- https://www.science.org/content/article/fda-advisers-greenlight-novavax-covid-19-vaccine
CureVac: filed a patent lawsuit against BioNTech and two of its subsidiaries in Germany for violation of MRNA patents
- An illustration of the competitive intensity in the Biotech industry over intellectual property protection, especially since CureVac’s MRNA-based COVID-19 vaccine was considered a failure
QazCovid-in (QazVac): WIV-based vaccine developed in Kazakhstan
- https://pubmed.ncbi.nlm.nih.gov/35770251/
Sinopharm: In June, reported a test of a Trivalent WIV vaccine in a mouse experiment; the test used the HBO2, Delta and Omicron variants - this is consistent with Refana’s approach
- https://pubmed.ncbi.nlm.nih.gov/35746564/

Financial Markets

Biotech stocks have suffered more than the general equity markets in the recent declines
- BioNTech down 35%; Moderna down 38%; Novavax down 63% over the past six months
- This compares to 16% drop in Dow Jones; 21% fall in S&P 500; 24% in the NASDAQ
Contrarian move: ARCH Venture Partners raised U.S. $3 billion to invest in early stage biotech

Post-COVID-19 Economy

While severely exacerbated by Russia's invasion of the Ukraine, all of the major economic shocks the world is now suffering were already evident/or predicted during the height of the COVID-19 pandemic, i.e.:
- Disruption to the global supply chain
- Labor shortages
- Rampant inflation
- Social unrest and political polarization

Refana Update

Refana's Vaccine Division maintains its interest in three areas:
- Design of longer-acting protective COVID-19 vaccine boosters using a Trivalent WIV approach
- Potentially dramatic improvements in the manufacture of WIV vaccines in terms of modularity (which lowers the economies of scale), quality and consistency of production (providing greater predictability and control of yields), and significantly improved unit cost economics
- The quest to design a single pan-Coronavirus vaccine - also known as a Universal Vaccine - utilizing computational genomics and Artificial Intelligence
Refana continues to seek non-dilutive funding for the first two areas and is exploring additional funding for the third area
Exhibit 3 shows the ‘Poster Board’ summary of the Illinois Institute of Technology (IITRI) research paper on the Refana-sponsored Proof-of-Concept WIV Vaccine Test - will be presented at the American Society of Virology (ASV) Conference in Wisconsin - July 16-20, 2022

Next Update - End of Q3

Exhibits

Exhibit 1: Cases Per Million People 2022

Exhibit 2: Deaths Per Million People 2022

Exhibit 3: American Society of Virology (ASV) Conference Poster Board - July 2022

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4/28/2022

SARS-CoV-2: From Vaccine Scarcity to Vaccine Demand Destruction and Vaccine Glut

The World Health Organization (WHO) shows no signs of removing the world-wide emergency Pandemic designation for SARS-CoV-2, but no new Variants of Concern/Interest announced
- Ongoing reports of further Omicron variant derivatives continue to appear around-the-world
However, world-wide vaccine demand has cratered, going from a mid-2021 7-day moving average peak of 43+ Million doses/day to 12 Million dose/day presently → 25% of peak demand
- More significant demand destruction in developed world → E.g., U.S. went from 3.5 Million peak demand doses/day in April 2021 to 300K doses/day currently → 10% of peak demand
- Current daily U.S. rates are now down to < 100K doses/day
Vaccine manufacturers have therefore curtailed vaccine production → E.g., Serum Institute of India (SII) stopped production in December 2021, with 200+ Million doses stockpiled
- World-wide SARS-CoV-2 manufacturing capacity is estimated at 9 Billion doses in 2022
- 2023 demand is estimated to be 2.2 - 4.4 Billion doses
Factors contributing to this demand destruction include: 1) Lowest global SARS-CoV-2 infection caseloads, hospitalizations and deaths since March 2020; 2) Lower SARS-CoV-2 measurement levels in most countries, except China, which is mass measuring under its Zero COVID-19 Policy; 3) Vaccination levels peaking in many developed countries; and 4) Concerns over waning immunity and safety issues with existing vaccines, further amplifying vaccine hesitancy
Despite 11.5+ Billion doses having been administered world-wide to date, Bloomberg estimates that at current vaccination rates, it will still take 11 months to achieve having 75% of the world population with at least one vaccination
- 12 Million doses/day X 11 months = almost 4 Billion more shots needed to hit this target
- Mostly to low-income countries, where 15% of people have only received one vaccine shot
- Consistent with Refana estimates that 2-3.5 Billion people still do not have access to vaccines

However, the Quest for Next Generation Vaccines Continues

To get to more effective vaccines, current providers - and new participants like Refana - continue to develop their next generation vaccines. Examples:
- Moderna testing a bivalent mRNA vaccine (Wuhan and Beta variants)
- RefanaVax-MV a trivalent WIV vaccine (Delta, Omicron variants + 1 more variant, as required)
- Moderna, Pfizer/BioNtech working on Omicron mRNA vaccines
- Moderna, Novavax working on combined SARS-CoV-2/Flu vaccines
Other attempts at nasal spray SARS-CoV-2 vaccines, more universal pan-coronavirus-based vaccines are ongoing → Longer-term development exercises

And WIV-based Vaccines Continue to Make Progress

Valneva’s WIV vaccine was approved by UK’s MHRA in mid-April
Valneva secured additional U.S. $40 Million in non-dilutive debt financing for WIV development
- Increases a ‘counter- cyclical’ bet to finance Valneva’s WIV vaccine - initially made in March 2020 - by OrbiMed/ Deerfield, two highly-regarded U.S. early-stage healthcare investors

Zero Covid Policies in China Leading to Massive Supply Chain Disruptions, Potential Global Economic Impacts

China continues to execute its Zero COVID-19 policy, including major city lockdowns in Shanghai (26+ Million people), and massive SARs-CoV-2 testing in Beijing (21+ Million people)
Since March, full or partial lockdowns in 20+ Chinese cities represents ~200 Million residents (13.6% of China’s population) and $3.6 Trillion (22%) of China’s economy
As reported last month, despite 3.3+ Billion vaccine doses administered in China (88+% fully- vaccinated rate), China still has > 130 Million residents over 60 years of age who are not vaccinated at all, or are under-vaccinated, and highly exposed to SARS-CoV-2 infections
Given this Zero COVID-19 Policy, the World Bank estimates China’s economic growth will decline from 8+% in 2021 to 5% in 2022, below China’s estimate of 5.5%. Goldman Sachs predicts 4.5%
World-wide impacts of this economic slowdown have not yet been fully-felt globally; with many countries so dependent on China for finished goods, this could lead to further global supply chain shocks and and an amplification of current inflationary trends experienced world-wide
- With predictions of a global recession becoming more and more prevalent.

Refana Update - Further Vaccine Developments

As mentioned last month, Refana’s vaccine is called RefanaVax-MV → MV = MultiValent
The Proof-of-Concept of the RefanaVax-MV monovalent (Delta strain) vaccine showed no safety/side-effect issues; all animals challenged with a 10X ‘fatal’ dose of Delta virus survived the challenge with no infection or disease symptoms
- Including an animal that showed no substantial neutralizing antibodies after the prime/boost regimen, suggesting protection was enabled by generating t-cell responses to the virus
The Illinois Institute of Technologies Research Institute’s (IITRI) research paper publishing these results has been accepted by the American Society of Virology (ASV) Conference in July 2022
Refana continues to work with a number of parties on funding proposals to NIAID, the National Institute of Allergy and Infectious Diseases, and to other parties for further stages of funding, which would take this Project further, to full trials and if successful, ultimate approval
Refana believes that the RefanaVax-MV WIV vaccine solution - coupled with Refana’s modular manufacturing system design - offers a strong solution for assisting with the current SARS-CoV-2 Pandemic and also to help the world prepare for the next Pandemic to come

Refana Update - Other Developments

As Refana’s vaccine developments continue, the company has begun to explore other medical solutions - building back to Refana’s founding investment thesis - to explore the application of Artificial Intelligence (A.I.) for focused medical applications
Further details will be provided when appropriate

Refana Communication - Investor Update

Given the currently reduced intensity levels of the SARS-CoV-2 Pandemic, Refana will change the distribution of this update from a monthly distribution to a quarterly distribution
With four Quarterly Investor Updates, Refana’s next update will appear on 30th June, 2022.

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3/31/2022

Covid 19 - Down, But Not Out

Despite the decision of many countries over the last two months to ease or eliminate COVID restrictions, it is clear that COVID is not over. There are a number of distinct themes:

The WHO still has COVID-19 classified as a world-wide Pandemic - the world celebrated the 2-year anniversary of that designation during March 2022
Many countries which have suddenly reopened, have experienced a surge in infections
- This includes many European countries, the UK, as well as selected areas in the U.S.
- The true extent of this may be hard to measure, as a number of countries, including the UK, cut back their testing programs shortly after re-opening.
A second factor is the rising prevalence of the BA.2 variant of COVID-19 (‘Stealth OMICRON)
- The WHO decided not to consider this a separate variant of concern, but rather to count this together with the BA.1 version of OMICRON
- This somewhat clouds the current trends, as we are having reports of people already infected with BA.1 getting another infection from BA.2
- Somewhat tellingly, the FDA has halted its approval of the GlaxoSmithKline therapeutic Xevudy Sotrovimab, which appeared to work against BA.1, as it doesn’t appear to work against BA.2
- Meanwhile the CDC estimates that half of all new infections in the U.S. are BA.2
A separate theme is what is happening in countries that were previously largely-closed and where Omicron has now penetrated
- The first case to note is Hong Kong, where infections rose dramatically from a very low base, but in the last week however, the infection rate in Hong Kong has dropped significantly
- Death rate in Hong Kong from this surge has been surprisingly high and it has been attributed to a significant proportion of older people, perhaps as much as ⅓, deciding not to be vaccinated for fear of the COVID vaccines, combined with their age and comorbidities
- As Hong Kong begins to regain control of the virus, a bigger question is China, where the major city of Shanghai and its 25 Million+ population is now under full lockdown - it has been estimated that as many as 130 Million 60+ year olds in China have not been vaccinated, given ‘vaccine hesitancy’ issues - similar to what was happening in Hong Kong

Attached in the Appendix, Exhibits 1 and 2 show the period of domination of the Delta variant, which accounted for nearly 100% of infections worldwide, running from June 2021 to the end of December 2021
- This is followed by the surge in Omicron infections in December and now causing nearly 100% of COVID infections worldwide
Exhibit 3 shows infection rates over the most recent seven days in six countries
- We see that while the infections in Hong Kong have fallen significantly, there has been a jump in infections in Germany, France, UK and Israel
- It is not clear if this is simply a short term effect due to the reopening programs of the relevant countries, or if it is a new wave triggered by the transmissibility of the BA.2 variant
As for death rates over the last seven days, there has been a noticeable increase in Germany
Infection and death rates continue to decline in the U.S., although there are regional variations

A final perspective worth considering, are the cumulative trends across these countries in infections and deaths
- Despite the enormous surge in Hong Kong over the last month, it is only at half the level, or less, of the other countries in cumulative terms of infections
- Even less in terms of deaths - see Exhibit 4
  - Cumulative death rate in Hong Kong - @ 982 per million - is close to the COVID death rate in Israel @ 1,128 per million
  - Both cumulative death rates are much lower than United States @ 2,936 per million
  - Major European countries fall between these extremes
- The significantly lower death rate (62% lower) in Israel compared to the U.S. appears to be due to the faster and higher take up of the initial vaccination campaign, followed subsequently by the third and in some cases fourth shots as boosters
- It may also be influenced - as in Europe - by the greater accessibility of national health services for the entire population

Concerns:

Are we seeing the start of a major BA.2 surge in Europe and elsewhere?
Will China now face widespread COVID infections which it appears to have avoided so far?

Refana Update - Proof of Concept on WIV Vaccine Yields Positive Results

We have tentatively named our vaccine RefanaVax-MV → MV = MultiValent
In our ongoing Pre-Clinical study @ IITRI in Chicago, mice were prime/boost vaccinated
Although vaccinated mice showed anti-Spike ELISA antibody titers, they also showed substantial neutralizing and ELISA titers after boost, against both the WA1/2020 and Delta variants (neutralizing titer of approximately 640 post-boost)
Vaccinated mice remained completely healthy, no side-effects from the vaccines
Protective efficacy of the vaccine was evaluated with a live SARS-CoV-2 challenge - a 10X ‘fatal’ dose of Delta virus → all the vaccinated mice survived
Details follow - these results suggest that the Refana WIV vaccine design against SARS-CoV-2 is robust and worth further developing

Table 1 - Neutralizing Antibodies vs. Wuhan Strain

Table 1 compares neutralizing antibody titres of the RefanaVax-VM Delta Variant COVID vaccine against the original Wuhan WA1 strain of COVID
None of the three vaccinated animals - TA 1, TA 2, TA 3 - nor any of the three control animals - initially had a measurable titre
- All < 40 at day 21 - 1st column
- By day 42, after the vaccine booster shot, two of the three vaccinated animals - TA1 and TA3 - developed good neutralizing antibody titres - 160 and 452 respectively - 2nd column
- These results compare with a titre of 1280 in the serum of a human who had recently received their third Pfizer vaccine booster shot

Table 2: Neutralizing Antibodies vs. Delta Strain

Table 2 has same structure as Table 1, but now measuring results vs. the Delta variant
As before, none of the control animals exhibited measurable neutralizing antibodies
However, all three vaccinated animals did have strong responses to Delta
- Two of the vaccinated animals - TA1 and TA3 - achieve a full threshold of the measurable titre in this experiment (= 640)
- Second animal TA2 achieved 56.6
In all cases, results achieved against the Delta variant are significantly stronger than what was achieved against original WA1 Wuhan variant
- Not surprising, as the RefanaVax-MV Delta vaccine was designed using the whole Delta virion
- This result is a mirror image of what occurred with the approved vaccines - all of which were designed against the original Wuhan variant and which subsequently showed lower levels of protection against the Delta variant
- RefanaVax-MV, used here, is a Delta specific vaccine, achieving a much stronger result
Our Chief Vaccine Advisors tells us that these results are about 3X better than what he has seen with other vaccine development Pre-Clinical studies

Table 3 - IGG antibody ELISA results

Table 3 shows the overall IGG antibody results from an ELISA test
Control animals had very negligible results on Day 21 - by Day 42 control animal number 1 had died from other causes, whereas the results from control animals 2 and 3 were still below a measurable range
All vaccinated animals had considerable levels of antibodies by Day 21, but with a more than 5x from the highest and lowest results - first column
The impact of the booster shot was to increase the IGG levels of all three animals significantly by between almost 5x to almost 9x - 2nd column

Challenge Results

All mice in the above study, both vaccinated with the Refana Delta specific COVID vaccine, and the unvaccinated control mice, were challenged with the live Delta virus
IITRI had previously established ‘LD50’ levels with respect to mice being challenged with live COVID virus, which led to the death of 50% of the mice in that cohort
This live challenge of the mice was at a viral content of approximately 10 times higher than the LD50 level - considered a ‘fatal’ dose
This massive dose killed all the unvaccinated mice
Vaccinated mice showed no symptoms whatsoever, including mouse TA2, which had exhibited very low neutralizing antibodies - as shown in the prior tables
- Presumably, TA2 was protected by the wider protective effect of the Whole Virion Vaccine, possible via stimulating a t-cell response

IITRI Paper - American Society of Virology (ASV) Conference - Wisconsin

See attached, Appendix 2, scientific paper abstract submitted to the ASV Conference
Presented at their annual conference in July 2022
- First in-person meeting in 3 years, given the Pandemic

Next Steps

Refana is now working with a number of parties on a funding proposal to NIAID, the National Institute of Allergy and Infectious Diseases, for next stages of funding, which would take this project, potentially, to full trials and if successful, ultimate approval

Appendix 1

Exhibit 1 - Covid Cases per Million People - 7 day rolling average

Exhibit 2 - Covid Deaths per Million People - 7 day rolling average

Exhibit 3 - Cumulative Covid Cases per Million People

Exhibit 4 - Cumulative Covid Deaths per Million People

Exhibit 5 - Delta Variant

Exhibit 6 - Omicron Variant

Appendix 2

Development of a Small Scale Whole Inactivated Vaccine Against B.1.617.2 SARS-CoV-2 Delta
Andrew Eaton1, Landon Westfall1, Dianet Giraldo1, Brian Maccaba2, Phillip Schwartz3 and Robert Baker1*

1 Affiliation 1: Division of Microbiology and Molecular Biology, Illinois Institute of Technology Research Institute (IITRI), Chicago, IL 60616
2 Affiliation 2: Refana™, Middletown, DE 19709
3 Affiliation 3: EnteraBio, Jerusalem Israel 9112002
*Correspondence: rbaker@iitri.org

Vaccine development against SARS-CoV-2 variants in humans will be benefited from using multiple types of vaccine constructs. Whole inactivated virus (WIV) vaccines are safe and have been used in the prevention of respiratory viruses such as influenza and polio as well as others, and have the added benefit of more stable storage. Here we have produced, inactivated, purified, and concentrated a Delta B.1.617.2 WIV and tested its efficacy using K18-hACE2 heterozygous mice. We compared varying growth conditions including serum-containing and serum-free medias. Total protein was quantified in both medias with values of 927 µg/mL and 2 µg/mL respectively. Following optimization of conditions, Vero E6 cells were grown in a Corning HyperFLASK® and infected with SARS-CoV-2 Delta (B.1.617.2). After harvest, virus was concentrated 500-fold using centrifugal filters and quality controlled at multiple steps using qPCR, Bradford, and SDS-PAGE. The original volume, prior to concentration, had a total SARS-CoV-2 genome content at 1.20E+11 copies. Following 100-fold concentration the total genomes copies was 3.78E+10 which correlates to a ~69% loss during processing. The final vaccine preparation was prepared with a squalene-in-water emulsion adjuvant and tested in K18-hACE2 mice along with shame-vaccinated controls. Mice were prime/boost vaccinated with a total of 0.2 µg and 1.9 µg S1 RBD, respectively. Although vaccinated mice showed only anti-Spike ELISA antibody titers, they showed substantial neutralizing and ELISA titers after boost against both the WA1/2020 and Delta variants (neutralizing titer of approximately 640 post-boost). Protective efficacy of the vaccine was evaluated with a live SARS-CoV-2 Delta challenge. These findings suggest that using a whole inactivated vaccine against SARS-CoV-2 should be further evaluated. A whole inactivated vaccine tend to be more temperature stable to reduce transport costs and associated issues to mitigate logistical challenges in delivering to other countries.

Key words:
Delta B.1.617.2, Whole Inactivated Virus Vaccine, Neutralization titers

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2/28/2022

Industry Updates Volume 17

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Omicron wanes, but leaves more death in its wake

Over the past four weeks, the number of new Omicron infections recorded in the U.S.A. has dropped dramatically from a peak of 800K+ on 15 January to just 66K on 26 February
A similar pattern has been seen in the European Union, where the peak of 1.25M+ infections occurred on 28 January and has now dropped to 475K
Total COVID deaths in the European Union just passed 1 Million and the U.S.A. has reached 950K

The Appendix shows that Rest-of-World countries did not suffer Delta and Omicron surges equivalent in magnitude to the more advanced countries
Even their smaller Omicron surges experienced, have also reduced substantially.

Europe Re-Opens - The "All Clear"?

While there are other minor variants being watched by the WHO, there does not seem to be an immediate threat of another highly virulent strain of COVID
Europe has mostly decided to ‘re-open’, including Denmark, UK, Greece, France, Portugal, Sweden and Norway - other EU countries are likely to follow
However, Omicron infections are currently still growing fast in Iceland, Singapore, Malaysia, South Korea, New Zealand and Hong Kong
- Note that most of these countries largely followed an ‘isolation’ or ‘Zero Covid’ approach.

Israel as a Case Study - Vaccination No Longer Counts?

Israel was the first country to inoculate most of its population with 2 shots; also the first to insist on 3rd shot, in order to retain a digital certificate required to attend events; and the first to offer a 4th shot
All shots were Pfizer
Despite the high levels of vaccination, 3.5M of Israel's 9.5M population got COVID
- 1.5M of them in the last 2 months
Israel has now ordered 5M shots of Novavax vaccine as a heterologous booster, although it is not clear if this will be deployed
Israel had severely restricted access for non-citizens over the past two years
From 1st March 2022, it is completely reopening its borders to all, irrespective of vaccination status
- Israel will no longer ask for proof of vaccination, but will require a PCR test before/after arrival.

Vaccine Equity - Africa

The % vaccinated in Africa has reached 18%, and sufficient supplies are now available and even now exceed the logistical ability to deploy them
The African Union has asked for a pause in supplies this month
Part of the log jam has been caused by widespread hesitancy to take a COVID vaccine
The debate about local strategic manufacturing goes on
- The WHO is working with Afrigen in South African to develop a near copy of the Moderna vaccine
- They have ambitious plans to manufacture this mRNA vaccine at 6 sites in Africa: Egypt, Kenya, Nigeria, Senegal, South Africa and Tunisia
- However without cooperation from Moderna there are doubts whether this will progress from the Lab to successful manufacture at scale
BionTech is promoting a 12 transport container ‘modular’ manufacturing facility that would be used to manufacture 40M doses/annually of the Pfizer/Biontech mRNA vaccine
- Still in development and likely not ready for deployment until 2023.

New Vaccines

Novavax’s protein-based vaccine is now available for use in 170 countries, including approval by the UK regulator, and has filed for use with 10 different regulatory agencies, including the U.S.A.
Canada’s Medicago COVID protein-based vaccine - based on tobacco leaves - now approved in Canada
Stephane Bancel, the CEO of Moderna, has stated that he believes the COVID Pandemic is now over, but annual boosters will be required.

Refana progress

Refana's Delta variant-based WIV COVID vaccine has successfully achieved its Proof of Concept (POC) objectives in our testing work at the Illinois Institute of Technology Research Institute (IITRI)
- The vaccinated transgenic mice exhibited good levels of protection
- There was a variation from low to extremely high protection between the mice
- The serum of the vaccinated mice successfully neutralized both the Delta and the Wuhan strains
- As expected for a Delta specific vaccine, the effect was noticeably stronger against Delta
The animals have not been subject to a live challenge
Refana should have the Proof of Concept report and full data tables next week
The Team is now exploring recently made available non-dilutive funding opportunities in both the public and private sectors that would enhance both our vaccine development and our modular manufacturing strategy
- Recent RFPs have been released by multiple agencies
- Refana is investigating its approaches to respond to those opportunities
- As these opportunities further develop, we’ll share more info on them with our Investors.

Appendix

Cumulative COVID-19 Deaths

Daily New Confirmed COVID-19 Cases

Daily New Confirmed COVID-19 Deaths

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1/31/2022

Industry Updates Volume 16

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Is Omicron the End of the Pandemic?

The consistent mood music in the media coverage of COVID-19 continues to suggest that the widespread infection by the Omicron variant will signal the end of the Pandemic as we know it
Globally, the daily infection rate is now at unprecedented highs of 3.3 million per day, which is more than four times the previous peak. Meanwhile the global death rate has also climbed significantly to 9,200 per day, one third below its peak of 14,700 per day in January 2021

Global new COVID-19 World Cases = 3.3 million per day

Global new COVID-19 Confirmed Deaths = 9,200 per day

The current daily death rate in the U.S. of 2,400 per day now exceeds the Delta peak by 20%, but it is still 1,000 deaths per day less than the peak deaths of 3,400 per day this time last year. The EU has a broadly similar pattern, with less deaths at the moment, but a significantly higher daily infection rate

COVID-19 daily case rate

COVID-19 daily death rate

Looking at the above data, it is clear that Omicron is not yet over, but possibly the decline in the infections seen both in the U.S. and the UK will be followed by Europe shortly, and the death rate will also trend downwards as infections fall.

What are the Assumptions Underlying the Hope that Omicron is the End of the Pandemic?

The implicit assumption is that Omicron infections are becoming so widespread around the world that it will protect us from further infection at the same scale in the future
The logical problem with this optimistic approach is that the Omicron variant which infected vast numbers of people irrespective of vaccination status or prior infection by different strains, will now protect us against new COVID variants
It may be reasonable to assume that infection by Omicron will also protect against a new variant like BA.2 which is not so different to Omicron, which is known as BA.1 in the United States
The difficulty will be if new variants emerge which are not similar to Omicron
Vaccination with a Wuhan strain-based vaccine did not protect against infection by Omicron
Prior infection with a different variant only partially-protected against infection by Omicron
So why should we expect that the billion or more people who will get an Omicron infection will have protection against different COVID variants in the future?
The practical way to consider Omicron as the end of the pandemic is the fact that the ratio of deaths to infection has improved almost four fold from more than 1% death rate a year ago to 0.28% today
We cannot tell for certain whether the dramatic reduction in death to infection ratio is a result of prior infections, vaccinations, or Omicron itself being more benign (for which there is some evidence, as it does not appear to infect the lower respiratory tract).

Where are Vaccines Going Next?

Pfizer has admitted that their vaccine provides limited protection against Omicron and both they and Moderna are promising Omicron specific vaccines in the next three months
Based on current trends, Omicron looks as if it will have long passed its peak by the time these vaccines are available
Some cynics have argued that after earning tens of billions of dollars providing a relatively ineffective vaccine, Pfizer was losing credibility by suggesting that a fourth or even fifth dose may be necessary and hence found it necessary to introduce a new product to replace the old one that is losing credibility
Very significantly Israel, which had been Pfizer’s closest partner from the start, last week purchased 5 million doses of the newly approved Novavax vaccine, sufficient to give further booster shots to over half the population
Refana’s Chief Vaccine Advisor, Stephane Paul, says that his scientific group expects further COVID variants to arise later this year and does not expect them to be similar to Omicron
The WHO and the U.S. Army are both sponsoring vaccine candidates that might provide more broad spectrum protection against different COVID variants and possibly other Coronaviruses, but none of these are expected to be proven, approved and manufactured at scale during 2022.

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12/31/2021

Industry Updates Volume 15

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28 Days Later: An Omicron ‘Remake’

The world is now at 285 Million cases, 5.4 Million deaths, 9.1 Billion vaccination doses
However, since being first detected in South Africa, Omicron has:
- Been detected in 100+ countries and all U.S. States
- Contributed to record caseloads, both world-wide, and across 20+ countries in 4 continents, including the U.S., Canada, the UK, France, Italy, Australia, Denmark, Ethiopia, and 7 other countries in Africa
- Already accounted for 59% of U.S. cases, along with 41% from Delta - acting like a ‘Twindemic’
- Demonstrated as being 70X more contagious than Delta - contributing to its rapid emergence
- Been so far seemingly less severe than Delta - but that lag in effect may bias hospitalization and death data, thus not yet revealing the complete story - experts are suggesting this wave needs to mature for a few more weeks into the New Year to get a clearer indication of severity levels
- Evaded current vaccines - typically requiring Boosters to get to sufficient protection - as well as some of the current therapeutic treatments
- Caused world-wide disruptions (e.g., Sporting events, concerts, New Years Eve celebrations, and the list goes on), led to thousands of flight cancellations each day, affecting Millions of travelers, and the complete shutdowns of multiple countries
- Reignited more actions and further debates/protests across multiple countries re: vaccine hesitancy and anti-vax, lockdowns, mandates, business shutdowns, school disruptions, delays on companies bringing employees back to work locations, etc.
- Pushed many locations to require proof of vaccination
- Led to a strong demand spike for infection testing, leading to a world-wide shortage of all test types - PCR, antigen/lateral flow, @ home testing, etc. - creating long testing line-ups, delays and frustration in getting results
- Demonstrated a general lack in preparation for such a rapidly escalating and contagious Variant of Concern, due to a lack of genetic sequencing, testing, stockpiling of therapeutics and deployment of next generation vaccines, all becoming key issues
- Elevated the potential of substantial further COVID-19 infections, e.g., modeling in the U.S. suggests that Omicron could infect up to 140 Million Americans from Jan-March 2022, vs 55 Million COVID-19 cases experienced so far in the U.S. - Note: Most of these infections will by asymptomatic, but will still act as carriers/transmitters of the virus

COVID Continues to Kill - Death Rate in High Income Countries up 6x in 5 Months

Notwithstanding the fast spread of a supposedly 'milder' version of COVID-19, the death rate has picked up in the High Income Countries. As shown in Exhibit 1 - This is not being reported generally and is counterintuitive, given that these countries are generally more highly and completely vaccinated
It is not clear whether the divergence in the death rate in High Income Countries compared to deaths in the Upper/Lower/Low Income countries is due to the different vaccines in use, or some other factor, such as under-reporting in those less-developed countries
However, with global COVID-19 daily caseloads currently now at all time highs (Exhibit 2), and given that the current number of weekly deaths is more than 50% below its previous peak, the death rate coming from the COVID-19 Pandemic overall has fallen
Current death rates are driven from the combination of the Delta and Omicron variants being the two dominant current COVID-19 variants
While Omicron is rapidly becoming the predominant strain, it is not happening as quickly as forecast
- In the U.S., the CDC revised its U.S. proportions of Omicron down this week vs. last week, but now has Omicron at 59% of all current U.S. cases, so the dominant variant in the U.S. over Delta
Lower death rates - despite record caseloads - are driven by multiple factors:
- The still protective effect of vaccines against worst outcomes, despite hundreds of thousands of breakthrough infections
- Natural immunity from prior COVID-19 infections
- Different age profiles of the infections - a much higher proportion of Omicron infections have appeared in younger, healthier people
- Better COVID-19 treatments and therapeutics, even as they show less effectiveness
- The possibility that Omicron is intrinsically less dangerous than prior variants

From Refana’s 2x2 Scenario Analysis of possible outcomes from the Omicron surge - Figure 1 here - it increasingly appears that we are seeing the lower right quadrant becoming dominant - Combination of higher transmissibility with less severe morbidity
- Driven by some combination of the five reasons outlined above

nThis “Extended Period of COVID-19 Restrictions” Scenario will likely lead to further Booster campaigns around the world, further exacerbating the current vaccine inequity/nationalism issues
Omicron-driven restrictions have become particularly pronounced with respect to travel. Examples:
- Many thousands of flight cancellations or disruptions world-wide
- Israel and Japan have restricted all foreigners from entering these countries
- Germany and France have banned the UK
- UK put the U.S. on its red list
- China has locked down 13 million people in a single city, given only 100 infections
It is questionable how meaningful these international travel restrictions are in reality, given that Omicron has already spread worldwide
- Indeed, the original travel ban on the Southern African countries has recently been revoked

Vaccines, Therapeutics and Vaccination in the West

At the margin, the existing Wuhan-strain Moderna vaccine shows greater protection than Pfizer, but Moderna’s CEO has still disclosed plans for an Omicron-specific vaccine
Living with an endemic COVID-19 virus for years-to-come is looking ever more probable, raising the inevitable question of ongoing vaccination strategies, leading to an ongoing need to update vaccines
Johnson and Johnson looks like it could exit the market, following recent negative comments from the FDA regarding further blood clot risks in younger healthy females
- However, as with the other vaccines, studies have shown that the J&J shot may still protect ‘enough’
Notably, AstraZeneca which has similar issues to J&J has still not received U.S. FDA approvals
A number of newer vaccines are coming forward - most significantly Novavax - which following multiple manufacturing-driven setbacks, has now received emergency approvals from the WHO and the EMA
The EMA has also placed an order for up to 60 million Valneva doses
- This is the first large-scale use of a WIV-base vaccine in the West
The FDA recently issued Emergency Use Authorizations for oral therapeutic drugs from Pfizer and Merck
- Both are moving to production - they will be expensive, costing $400-$700 per treatment course, vs. $5 - $40 per dose costs for vaccines
- The U.S. placed a $5.3 Billion order for Pfizers’s Paxlovid drug - 10 Million treatment courses (likely less than expected demand) - some Paxlovid is available now, more to come in next 6 months
- Paxlovid is claimed to have an almost 90% efficacy in preventing a need for a hospital stay for a COVID-19 infected patient
- Some emerging issues of side-effects with the Pfizer and Merck therapeutics have been noted, along with Merck’s efficacy dropping from being only at 50% to 30% in more detailed trials
- Refana was surprised that the FDA approved the Merck therapeutic

Differential Death and Vaccination Rates

Exhibit 3 shows significant differences in ‘excess death rates’ since last year
These excess deaths can be due to COVID-19 infections and also additional deaths arising as an indirect effect of COVID-19, such as under-treatment of other ailments
In most countries, the ratio of reported COVID-19 deaths to the overall excess mortality is consistent
- Russia is an exception - they may have been only reporting approximately 20% of COVID-19 deaths
Exhibit 4 shows significant differences in the vaccination/Booster rates world-wide, by country - the U.S. represents approximately a ‘median’ position in terms of vaccinations
- Countries with equal/lower vaccination rates than the U.S. have higher cumulative death rates
- However the correlation does not appear to work in the opposite direction, i.e., that as vaccination rates increase above the average in the U.S., this does not correlate proportionally with lower cumulative death rates
- It appears that as vaccination rates increase above the U.S. threshold, the more significant reduction in the cumulative death rate are driven by the additional public health measures and degree of compliance, as indicated in Japan, Canada, Israel, Germany, Sweden and France
Exhibit 5 shows that the Upper Middle Income countries have now fully caught up with - even slightly exceeded - the vaccination rates of the High Income countries
- Lower Middle Income countries are at half this level and should catch up on a two-shot basis (but probably not Boosters) during 2022
- Lower Income countries however are still only at 12 vaccinations per 100 people, which, on a two-shot vaccine regime, is only a vaccination rate of 6% of the population
Without a major change in global policies and cooperation, many countries world-wide are unlikely to achieve satisfactory vaccination levels in 2022

Three Key Questions

Is Omicron the ‘last’ major Variant of Concern, leading to a final transition from COVID-19 Pandemic to Endemic, and a need for ongoing maintenance (i.e., Boosters) against localized flair-ups of COVID-19?
Or, will other Variants of Concern continue to emerge from less vaccinated areas of the world, or from emerging ‘reservoirs’ of COVID-19 virus in animals, e.g., white tailed deer, rats, dogs, cats, etc.?
When will the world begin to collaborate more constructively to solve the COVID-19 Pandemic, getting to more consistent and complete world-wide vaccination rates and the ability to combat local/regional outbreaks of the disease?

Outlook for 2002

Numerous commentators are predicting a ‘new normal’ in 2022, where we will have to learn to live with an Endemic COVID-19
The implications are that with the ever greater availability of vaccines from the second half of 2022, an increasing proportion of the entire world's population will be vaccinated
Ongoing Booster vaccination campaigns are to be expected for the coming years, with the frequency determined by the speed with which vaccines wane and the frequency and severity of highly transmissible or dangerous new variants
Refana predicts that the recourse to travel bans, lockdowns and long quarantine periods will be abandoned progressively during 2022 as the futility of these actions becomes ever more apparent
What the world is waiting for is a next generation vaccine that is more effective in: 1) The duration of the protection it provides and 2) Being able to further withstand new Variants of Concern - which is exactly what Refana is working on
- This appears to be the only ‘Silver Bullet’ on the horizons in Leading Countries

Refana Update

Refana’s validation of its Delta-specific vaccine is continuing in a pre-clinical trial at the Illinois Institute of Technology Research Institute (IITRI) in Chicago
The transgenic mice, who have the ACE 2 human gene receptor, received their first vaccine shot three weeks ago, and will receive their second shot next week
Meanwhile IITRI will commence growing the certified Omicron virus strain they received from the CDC
Refana’s larger trial will now seek to test a bivalent vaccine - using both the Delta and Omicron variants - on a statistically valid number of animals, and in a comparison with mRNA vaccines

Follow this link to see the graphs and insight in exhibits 1-5

Exhibits 1-5

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12/31/2021

Refana End Of Year Analysis of COVID-19 Trends

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COVID-19 death rates in the high income countries have increased 6x in 5 months

The current death rate in the advanced economies of 3 per million per day is now four times the average death rate in the rest of the world. Is this because of the reliance on mRNA vaccines?

Exhibit 1 - Death Rates Per Capita Across High to Low Income Economies

Exhibit 1 shows the death rate per million people on a daily basis from COVID-19
Since the start of the pandemic in early March 2020 until today, there have been 5.4 million deaths which is an average death rate of 8,000 deaths per day; with a world population of 7.8 billion, this is approximately 1 death per million per day throughout the pandemic
The exhibit shows that actual deaths per day worldwide per million previously peaked at 1.85 per day in mid January 2021 - the current death rate worldwide per million is now at < half its peak, at 0.8 per day (see red dots on Exhibit)
In the High Income countries - who have very high vaccination rates with mRNA vaccines and the best medical care in their hospitals - the all-time peak in death rates per million was 6.7 per day at the end of January 2021. This fell to a low point of 0.47 per day in late July 2021
- However, since late July 2021, the death rate per million from COVID-19 has increased from 0.47 per day to a current figure of 2.81 per day. This is an increase in the number of deaths of 6X in the High Income countries in the last 5 months
Exhibit 1 shows a dramatic divergence in the huge increase in the death rate in the High Income countries compared to the lower and declining death rates in Middle/Low Income countries

One explanation may be the differences in the vaccines used:
- mRNA vaccines used predominantly in the High Income countries quickly lose their protective effect
- Vaccines used predominantly in the rest of world are currently the Chinese or Indian WIV vaccines
- If WIV vaccines are providing better protection, it may not be due to neutralizing antibodies - as these have been shown to decline quickly for all vaccine types
- This extra protection might possibly due to the wider protective effect of a whole virus WIV vaccine

Exhibit 2 - New Covid Infections per Capita across High to Low Income Countries

Exhibit 2 shows that the global daily new infection rate per million for COVID-19 has hit an all time high of 152 per day this week, which is 83% higher than its previous peak of 83 per day at the end of mid-August 2021, and is more than twice the level of 71 per day at the end of December 2020
Compared to this, the High Income country infection rates now are off the charts - running 5.4X the global average, at a rate per million of 816 per day, compared to the global average of 152 per day
The daily infection rate per million in the High Income countries has jumped from 77 per day at the end of June 2021, to 816 per day today, an increase of 10.6X in the past 6 months
Conversely the Middle/Lower Income countries have substantially lower, declining rates of infection
Again, this may be due in part to the different vaccines used in the high income countries, where they rely almost exclusively today on mRNA while the rest of the world is majority WIV vaccines

Exhibit 3 - Excess Mortality Rates for Selected Country

Exhibit 3 - Excess Mortality Rates for Selected Countries

Exhibit 3 provides another way of looking at the data on deaths, as there are inconsistencies in attributing deaths to Covid-19 in certain countries
The number of ‘excess deaths’ is calculated by comparing the current number of total deaths compared to what the previous trend line would have predicted had COVID-19 not occurred
These excess deaths may be due directly to COVID-19 infections and also any additional deaths arising as an indirect effect of COVID-19, such as under-treatment of other ailments
In some countries, such as Japan and Germany, the protective measures taken as a result of COVID-19 actually lead initially to an overall reduction in the number of deaths
However, in most countries, the ratio of reported COVID-19 deaths to the overall excess mortality is reasonably consistent, with the one glaring exception of Russia, which based on Exhibit 3, has the worst results of any reporting countries, other than Peru
- Russia appears to have been under-reporting by approximately one-third of COVID-19 deaths
Data is not available to calculate equivalent numbers for China, India and the Lower Income countries

Exhibit 4 - Vaccine/Booster Doses - Selected Countries

Exhibit 4 shows the current vaccine status for the same countries shown in Exhibit 3
In both cases, the U.S. represents approximately the ‘median’ position in terms of vaccinations
It is very noticeable that the countries with equal or lower vaccination rates than the U.S. all have significantly higher cumulative death rates
However the correlation does not appear to work in the opposite direction, i.e., that as vaccination rates increase above the average in the U.S. this does not correlate proportionally with lower cumulative death rates
Therefore, it appears that as vaccination rates increase above the U.S. threshold, the more significant reduction in the cumulative death rate are driven by the additional public health measures and degree of compliance, as may be indicated in Japan, Canada, Israel, Germany, Sweden and France

Exhibit 5 - Vaccine/Booster Doses by High to Low Income Countries

Exhibit 5 shows that the Upper Middle Income countries have now fully caught up with, and even slightly exceeded the vaccination rates, of the High Income countries
The Lower Middle Income countries are at half this level and should catch up on a two shot basis (but probably not Boosters) in the course of 2022
Lower Income countries however are still only at 12 vaccinations per 100 people which, on a two dose vaccine regime - this is only a vaccination rate of 6% of the population
Without a major change in global policies and cooperation, many countries world-wide are still unlikely to achieve satisfactory vaccination levels in 2022

Industry Update Volume 15

Thanks to 'Our World In Data' for the fantastic graphs.

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11/30/2021

Industry Updates Volume 14

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From the Known…

Global impacts to date: 260+ Million confirmed cases, 5.2+ Million confirmed deaths
Delta variant-driven caseloads increasing again world-wide - some locations back to previous highs
- This has led to lockdowns and/or severe restrictions in Europe (e.g., Austria, Germany), tightening in the UK, and significant caseload increases and selected restrictions in the U.S. and Canada
- Three European countries experienced riots over the past two weeks - protestors reacted to the increasing social restrictions and the threat of compulsory vaccine mandates to combat Delta surge
- U.S. caseload range.: Florida (best) at ~30 cases/100K, Michigan (worst) at ~390 cases/100K (7 day rolling average) - a 13X difference
- Multiple court challenges ongoing against U.S. vaccine mandates
- Dr. Scott Gottlieb, former FDA Commissioner, hypothesizes that with waning vaccine immunity levels, the number of “breakthrough’ infections is much larger than what is being reported
~8 Billion vaccine shots administered globally; however, 70% of these in 10 countries; 30% in China
- According to the WHO, for every 100 people in high-income countries, 133 doses of COVD-19 vaccine have been administered, while in low-income countries, 4 doses per 100 people have been administered → Clear indication of ‘Vaccine Nationalism’ at play
In the U.S., recent CDC analysis suggests that if someone is not vaccinated, they are:
- 5-6X more likely to get infected with COVID-19, even if previously recently infected
- 10X more likely to end up in hospital if infected
- 11X more likely to die from COVID-19

Fully-vaccinated people make up less than 1% of COVID-19 deaths in the U.S.

...to the Highly Unknown - Omicron Variant (Breaking News - Refana is Monitoring Carefully)

We have entered a frequently predicted - and almost inevitable - situation, where a major new, highly differentiated, variant has emerged from countries with much lower vaccination rates → Omicron
World Health Organization and others have been warning for months that Vaccine Nationalism and hoarding of supplies by the richest nations would ultimately prove counterproductive
Many large populations, for example in Africa, are still almost completely unvaccinated, and thus remain strong breeding grounds for new strains of COVID-19
Despite all these prior warnings, Omicron’s emergence seems to have caught the world unprepared
So far, small numbers of Omicron cases have been detected in multiple countries - including Australia, Belgium, Botswana, Canada, Denmark, Germany, Hong Kong, Israel, Netherlands, UK, and South Africa - suggesting that the variant is already spreading (Note: Current data is quite limited)
Many countries - including the U.S. - have already banned flights from 8 countries in Southern Africa
- This may prove futile if Omicron didn't originate there, or has already escaped in sufficient volumes over the past 2-4 weeks before the initial sequencing in South Africa identified this new variant
Israel and Japan have banned all travel with incoming foreigners
- Fully-vaccinated returning Israelis - even w/negative PCR tests - will need mandatory quarantining
- These measures were introduced for two weeks, to give time to assess a more complete risk profile
The severity of Omicron infection, and its ability to overcome vaccinations, is unknown at this point

Currently the world is lacking key information about this new variant - other than the highly concerning point that Omicron has 50 mutations, of which 32 are on the Spike Protein
- This suggest that the Spike Protein-based vaccines’ ability to protect may be further weakened
- Both mRNA manufacturer CEOs have publicly reiterated this point this over the past few days, building on Pfizer CEO Alber Bourla’s similar comments from six months ago
- However, Refana has previously observed that 'WIV-centric’ countries have suffered much less severe Delta surges than 'mRNA-centric’ countries
Regeneron and Eli Lilly have already reported their COVID-19 therapeutic solutions are less effective vs. the Omicron variant; no updates yet re Omricon’s impact on the Pfizer/Merck/AstraZeneca solutions
- Meanwhile, Merck’s efficacy levels have been lowered from 50% to 30%, given further testing
South Africa has protested that it is being unfairly punished for ‘discovering’ this variant
- For both the Alpha strain, discovered in Britain, and the Gamma strain, discovered in South Africa, there was no evidence that those variants had actually emerged in those countries
- Rather, they have much better testing and sequencing infrastructures than their neighbors
The timing of Omricon’s arrival is unhelpful:
- The recent world-wide unrest and protests to the restrictions, mandates and lockdowns could further amplify if these measures need to be strengthened
Dr. Scott Gottlieb, former FDA Commissioner, summarized the current Omicron situation well over the past weekend (28 November 2021): https://www.cbsnews.com/news/transcript-dr-scott-gottlieb-on-face-the-nation-november-28-2021

Four Omicron impact scenarios are possible → Scenario likelihoods will not be clear for at least 2-6 weeks (Figure 1)
- Omicron could prove extremely dangerous and prolong COVID-19 as a Pandemic by 12-18 months, requiring new vaccines, and new campaigns with 2-3 shots each
- Omicron could also prove either largely irrelevant, or even be somewhat benign

Increasing Infection, Decreasing Deaths?

While new infection rates from Delta had already climbed dramatically in many countries - and death rates have also climbed - the impacts are not as bad as in previous waves
- This is evident even in countries with very high vaccination rates, e.g., Ireland, which has experienced high levels of breakthrough infections with Delta
- Very roughly, it could be said that the death rate has fallen from 2% to <1% of those infected with Delta, compared to the earlier death rates from prior strains
- This does not mean that Delta is inherently less dangerous
- Indeed, Delta could be significantly more dangerous on its own, but the combined impact of higher vaccination rates and more effective treatments have helped reduced the death rate by half
It is important to bear this in mind in analyzing the threats of Omicron
- If the Omicron variant breaks through the current generation vaccine protection firewalls, overall COVID-19-related death rates could rise again

Industry/Market Responses to Omicron

Omicron is likely to force the Western market leaders - Pfizer and Moderna - to do what they have been reluctant to do - drop their extraordinarily profitable current products and pursue new vaccine approvals
- It is arguable from a medical perspective that they should have already introduced specific anti-Delta vaccines, as the efficacy has waned to 46% and 58% respectively
All manufacturers are already running tests of existing vaccines against Omicron
Some have begun Omicron-specific booster development, as well as to explore other solutions
Even though the Regulators could allow smaller human testing e.g. 800 vs 15,000 vaccine recipients, there are always uncontrollable, unknown factors in a clinical trial, which could put current providers’ $30 Billion Covid vaccine business at risk
- It is unlikely that they will be able to achieve the 94-95% efficacy they reported the first time, as those trials had unusually favorable factors, e.g., U.S. sample only, no new variants, and apparently ‘softer rules’ allowing the exclusion from the calculations of non-symptomatic cases, combined with a political environment wanting a ‘positive’ result
- Given the disappointment with the rapid declines in vaccine effectiveness, and with the greater COVID-19 knowledge today, there could be greater regulatory scrutiny this time, depending on the frequency/severity impacts
However, If the more dangerous impact scenario emerges from Omicron, regulators could weigh the cost/benefit tradeoffs of human testing vs. in vitro lab testing of new vaccine formulations - as is currently done annually for the flu - this is speculative, but was also suggested by an mRNA CEO
On the WIV side:
- Experts in the UK have stated that because a WIV vaccine has more parts of the virus for the immune system to learn from it could be more ‘variant-proof’ than the others
- European Union has ordered up to 60 million WIV vaccines from Valneva
- Sinovac has recently re-engaged with the EMA as to a potential European approval and market entry
Global investor markets have become rattled and volatile, given the news of the Omicron variant

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10/29/2021

Industry Updates Volume 13

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Living with the Endemic

November will be the month when the Covid Pandemic officially becomes Endemic, based on the agreement of the United States and Europe to adopt an open skies without a quarantine policy for vaccinated persons.
This decision is driven more by political and economic considerations, than by medical or epidemiological facts.
The UK currently has extremely high infection rates (~ 50K per day, and going higher), as do several countries in central and eastern Europe.
Singapore, which had tightly controlled the pandemic for a long time, has now been placed on the highest category 4 travel warning by the CDC, as infections have surged.
Israel has asked the U.S. and Europe to treat any traveler who has been vaccinated for more than 6 months, as if they were unvaccinated if they have not received a booster shot, but this request has fallen on deaf ears.
China, Europe, and North America are all now reaching vaccine plateaus, and India, several other Asian countries, and much of Latin America will also reach this point by Q1 2022.
There are sizable remaining pockets of unvaccinated in several countries, including the U.S.
With 6.6 Billion COVID-19 vaccine doses administered worldwide to date, there are still at least 4-5 Billion people that have not been vaccinated at all, or just partially vaccinated.
The World Health Organization and the Covax facility are again complaining that very few vaccines are available for Africa and a number of other poorer countries as richer countries are buying up all the available supplies for booster shots and to create strategic stockpiles.
Living with the Endemic is likely to mean booster shots every six to twelve months for the foreseeable future.

What Does the Medicine Say?

The original strategy of achieving 'herd immunity' has been quietly dropped as the volume of breakthrough infections show the theory to be untenable with respect to Covid.
National health policies say that vaccination will reduce the risk of a subsequent infection by over 50%, AND, will also reduce the risk of a severe outcome if infected by a further 50%.
In addition, care of Covid cases has improved, and new therapeutics such as the Merck pill may reduce severe illness by a separate 50%.
The cumulative effect of all of this is to reduce the risk of death from Covid for people with up to date vaccination by over 90%, so that the disease becomes 'manageable'.
Merck has now offered to allow free licensing of its Covid therapeutic pill in poorer countries
It looks like we will be living with an ongoing but much lower death rate from endemic Covid for many years to come.
The great unknown is whether new variants which are more dangerous than Delta will emerge, or conversely will the virus naturally wane over time.
Circumstantial evidence continues to suggest that countries which used the broader spectrum WIV vaccines have suffered less in the Covid surge as illustrated in the following graphs:

Source: Our World in Data as at 23rd October 2021

The FDA and CDC made an important decision to recognize the evidence from research studies that heterologous vaccination (using a different type of vaccine as a booster) is more protective than more of the same vaccine, and has approved this approach.
Some of the underlying research proving this was conducted by a team including Refana's Chief Vaccine Advisor, Professor Stephane Paul.
Given the waning efficacy of the original vaccines, we expect a significant number of new products to be introduced during 2022, including formulations by Pfizer-BioNTech and Moderna.

The Business of Vaccines

The value of Covid vaccine sales in 2021 and 2022 is such that the category is becoming the most valuable drug category of all time.
Pfizer-BioNTech and Moderna are enjoying profit margins of over 70% on their sales.
A number of recent business articles have noted that the 2 big 'vaccines winners' were 'outsiders' - the Turkish Muslim husband and wife team who founded BioNTech in Germany, and the Boston based Moderna founded by an Armenian immigrant, and with a French CEO and Israeli Chief Scientist.
Conversely none of the three major historic vaccine companies Merck, GSK and Sanofi got a vaccine to market. While Johnson and Johnson, and AstraZeneca (licensed from Oxford) did get to market, they have had much less favorable market share and overall economics.
Pfizer has proven itself as an excellent manufacturing and sales partner to BioNTech, but despite its dramatic revenue and profit surge expected this year and next, this is not reflected in the share price, as Pfizer failed to agree an acquisition or long term strategic deal with BioNTech, which continues to control the underlying technology.
The situation with the Chinese manufacturers Sinovac and Sinopharm is less transparent but consulting firm Airfinity expects they will each hit $20bn of revenue this year, based on over 2 billion shots delivered in China, and more than a billion overseas. The great unknown however is the pricing deal with the Chinese government.
For conspiracy theorists, the fact that China has proceeded with a 100% WIV domestic vaccination program that now covers 80% of its population is a Red Flag!
China had access also to adenovirus vaccines, like AstraZeneca, J&J, and the Russian Sputnik V. Having acquired 6 Million doses and administering them to the Chinese security forces, they suddenly stopped using it without comment. What do the Chinese know that we don't?
Refana estimates the value of the Covid vaccine market, based on the need to provide boosters, and to protect from new variants, to be worth U.S. $180 Billion from 2023-27.
Current global volumes of doses administered to date by vaccine type are set out below.

Source Wikipedia. Correct as at 30 September 2021

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9/30/2021

Industry Updates Volume 12

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State of the Pandemic - Still Raging, Even Though Everyone is Getting Tired Of It!

The global pandemic continues to rage, as the worldwide death toll fast approaches 5 Million, and confirmed global Covid infections are now close to a quarter of a Billion.
Deaths in the United States are almost 700,000, followed by nearly 600,000 in Brazil, and 450,000 officially declared in India (but widely believed to be under-reported).
The total Covid death rates per Million in the United States and the UK are almost identical (2,098 and 2,090) but far exceeded by Peru and Brazil (6,131 and 2,831).
Latin America death rates (Mexico, Argentina and Columbia) exceed the U.S./UK death rates, as do several European countries (Italy, Belgium, Czech Republic, Bulgaria, Hungary, Croatia)
Some countries have notably lower death rates (Canada 738; Israel 848; and Ireland 1,054).

However, daily new infections have been close to previous peaks as the Delta surge continues.
The daily death rate is lower than previous results. Global deaths peaked at over 17,000 per day in the January 2021 surge; at 15,800 in the April surge; but peaked at 11,700 in the current surge at the end of August, and have now fallen back to approx 7,000 death/ day
Of these 7,000 daily deaths globally in late September, up to 2,000 have been in the United States as the Delta variant continues to spread.
Lower total deaths overall during the latest surge may be a result of global vaccination, where over 6 billion shots have now been given, with 40% of these in China (which now exceeds 80% inoculation, based on reported numbers.)
In the United States - and other western countries - the vaccination campaign has bifurcated into two different groups:
- Extending vaccination to younger age groups, while also combating the 15-30% of 'hold-outs' who have not been vaccinated.
- Providing 3rd 'booster' shots, as vaccine efficacy - particularly of market leader Pfizer - BionNTech - has waned significantly over 5-8 months, and less effective against Delta.

The Biden administration is making concerted efforts to increase vaccination rates - using a 'carrot and stick' approach. Compulsory vaccination is required in many workplaces. At the same time, the U.S. and Europe have agreed to re-open the skies for mutual travel without quarantine - but only to the vaccinated - from November.
The ‘hold-out’ rate in the United States has declined a little, following the Delta surge, but still stands at 25% of eligible adults, who have declined the Covid vaccine.
In Israel, the hold-out rate of unvaccinated adults has fallen from 23% to 17% following Delta, and the 3rd shot campaign for the rest of the population.
Overall, the U.S. ranks last of G-7 countries in overall vaccination rates, recently passed by Japan.
Conversely, certain countries - including Canada and Ireland - exceed 90% vaccination of eligible adults. Ireland has taken first place in the Bloomberg ranking of Covid resilience, while the U.S. fell to 28th place and Israel to 41st.

Delta has Quietly Changed Public Policy

High rates of breakthrough infections caused by the Delta variant - combined with the waning immunity of current vaccines - has prompted an effective, if unannounced, change in public health policies worldwide.
- Actual infection by Covid has been shown to provide 13 times more protection against reinfection than 2 shots of the Pfizer-BioNTech vaccine.
The case for vaccinations being made is that it reduces the risk of severe outcomes like hospitalization and death by 80-90% in those infected by Delta, and NOT that it protects directly against infection or transmission.

Covid 19 Vaccinations

Given the high rate of breakthrough infections from Delta, the potential community protection of 'herd immunity' is elusive.
See attached figure showing vaccination rates of the ‘best’ countries in the world - even they are not good enough.
McKinsey estimates vaccination rates needed by countries to achieve herd immunity. Ranges from ~100% vaccination in isolated countries like Australia - which have had little natural infection - to < 50% in countries like Brazil.
A key change in the McKinsey model - they assume that "Natural infection is ~100% effective, lasts long enough to reach herd immunity".
In the U.S., sharp differences have emerged between the White House, the FDA and the CDC re: policies for further booster shots of existing vaccines, leading to the resignation of two senior FDA vaccine officials.
Data is not clear whether boosters provide much additional protection to healthy younger adults, but have been recommended for the 65 plus by the FDA, and approved for a wider audience to include younger people with weakened immune systems by the CDC.
The absence of a vaccine which could directly protect against the Delta variant has become evident in this debate - most officials believe that the pandemic will become endemic, with further new variants arising.
Albert Bourla, the CEO of Pfizer, has said that he expects that current vaccines may not be protective against new variants which may arise after Delta.
It is not clear whether issues facing countries which have relied primarily on mRNA vaccines from Pfizer and Moderna (e.g. U.S., UK, Israel) will also apply to countries which have relied primarily on other vaccines, and particularly Whole Inactivated Viral (WIV) vaccines.
If natural infection with the whole virus has been shown to be 13 times more protective than Pfizer after 6 months, then a vaccine which most closely replicates natural infection (a WIV vaccine) should also provide wider, longer term protection.
Four important charts showing infections and death rates included below.

Covid Deaths

Covid Deaths per million people

Confirmed Covid Cases

Confirmed Covid Cases per million people

What the World Needs Next: Market Opportunity

Our conclusion is that what is now urgently needed is a WIV vaccine manufactured and regulated to the top western standards, based directly on Delta and other latest variants.
This would be a meaningful 'booster' for those already inoculated with a Wuhan strain Spike protein vaccine; as well as a much more direct protection for the unvaccinated everywhere.

Graphs courtesy of Our World In Data

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Industry Updates Volume 20

SARS-CoV-2: Tougher Variants, New Vaccines, Extended Coverage, Slower Vaccine Rates

Exhibits

Industry Updates Volume 19

SARS-CoV-2: From Vaccine Scarcity to Vaccine Demand Destruction and Vaccine Glut

Industry Updates Volume 18

Covid 19 - Down, But Not Out

Challenge Results

IITRI Paper - American Society of Virology (ASV) Conference - Wisconsin

Next Steps

Appendix 1

Appendix 2

Industry Updates Volume 17

Appendix

Industry Updates Volume 16

Industry Updates Volume 15

Refana End Of Year Analysis of COVID-19 Trends

COVID-19 death rates in the high income countries have increased 6x in 5 months

Exhibit 1 - Death Rates Per Capita Across High to Low Income Economies

Exhibit 2 - New Covid Infections per Capita across High to Low Income Countries

Exhibit 3 - Excess Mortality Rates for Selected Countries

Exhibit 4 - Vaccine/Booster Doses - Selected Countries

Exhibit 5 - Vaccine/Booster Doses by High to Low Income Countries

Industry Updates Volume 14

Industry Updates Volume 13

Industry Updates Volume 12

Categories

Archives

SARS-CoV-2: Tougher Variants, New Vaccines, Extended Coverage, Slower Vaccine Rates

Exhibits

SARS-CoV-2: From Vaccine Scarcity to Vaccine Demand Destruction and Vaccine Glut

Covid 19 - Down, But Not Out

​Challenge Results

IITRI Paper - American Society of Virology (ASV) Conference - Wisconsin

Next Steps

Appendix 1

Appendix 2

Appendix

COVID-19 death rates in the high income countries have increased 6x in 5 months

Exhibit 1 - Death Rates Per Capita Across High to Low Income Economies

​Exhibit 2 - New Covid Infections per Capita across High to Low Income Countries

Exhibit 3 - Excess Mortality Rates for Selected Countries

Exhibit 4 - Vaccine/Booster Doses - Selected Countries

Exhibit 5 - Vaccine/Booster Doses by High to Low Income Countries

Categories

Archives

Challenge Results

Exhibit 2 - New Covid Infections per Capita across High to Low Income Countries