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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.