Blog Posts

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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9/3/2021

Covid-19 Vaccines - Is Anything Better Than mRNA?

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Recent analyses of populations experiencing further waves of COVID-19 infection based on the Delta variant indicate that new challenges are emerging in the fight against the COVID-19 Pandemic: Some in-use vaccines are failing to provide long-run protection against the rapidly evolving COVID-19 virus, whereas others appear to be showing better long-term performance. See our analysis in our Industry Update 11.

For example: Double vaccination protocols with Pfizer/BioNTech’s mRNA-base COVID-19 vaccine in Israel did NOT prevent most infections by the Delta variant, although the protocol does reduce the risk of hospitalization for serious COVID-19 illness
Given that Pfizer/BioNTech’s vaccine does not prevent either infection and/or transmission of the Delta variant in many cases, the concept of ‘Herd Immunity’ against Delta becomes moot
- Most COVID-19 policy-decisions world-wide are largely driven on the objective of achieving herd immunity
Israel’s analysis of recovery from a prior natural COVID-19 infection had determined that it provides protection against the Delta variant that is 10X – 13X+ times more powerful than the protection provided by the current Pfizer/ BioNTech two dose protocol
- This has important implications on the need for/frequency of booster shots to maintain strong immunity levels, along with the need to frequently update the vaccine formulations to ‘keep up’ with rapidly evolving COVID-19 variants

Israeli Ministry of Health figures illustrate how two shots of the Pfizer/BioNTech vaccine is providing very little protection against the Delta variant.

Alternatively, evidence is emerging suggesting that vaccines based on the whole virion (Whole Inactivated Virus – WIV vaccines) are providing better and longer-range immunity and protection against the most recent variants
- Driven by the WIV vaccine’s basic structure which is similar to the natural infection of COVID-19 and exposes the immune system to the whole virion, not just the Spike protein

Image from Our World In Data

Data from countries relying substantially on WIV vaccines are NOT experiencing a Delta surge comparable to countries relying predominantly on Spike protein-only vaccines.

There also appear to be marked differences in your immune system after a natural infection with coronavirus and after vaccination.
A substantial amount of research suggests that a second or third shot of a DIFFERENT type of vaccine appears to provide greater protection than more shots of the same. This finding however appears to have been ignored in both the Israeli and US booster shot decisions.

The current situation with vaccines world-wide strongly supports the following hypotheses:

A whole virion (WIV) vaccine creates an immune response that is much closer to actual infection from Covid, as compared to vaccines relying solely on the Spike protein
A whole virion WIV vaccines will therefore provide significantly higher protection against the Delta surge
Any Covid vaccine modeled directly on the Delta variant will provide more protection than the SAME vaccine modeled on the much earlier Wuhan strain (i.e., all current vaccines)
An ideal vaccine should carry 'multiple payloads' as there will be further evolution of new variants, most likely continually derived from the now dominant Delta strain.

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8/25/2021

Industry Updates Volume 11

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Global Covid Pandemic - Booster shots against the Delta variant

The pandemic has entered a significant new phase with the approval of 3rd, 'booster', vaccine shots in Israel and the United States, and similar approvals are expected shortly in the UK, Canada, Germany, France and elsewhere. This has been criticized by the WHO as worsening the vaccine shortage for poorer countries.
The first such decision, in Israel, was due to the inability of double vaccination by the Pfizer- BioNTech mRNA vaccine to prevent Covid infection by the Delta variant. Despite having had the fastest full vaccination program in the world, the infection rate since Delta is as high as the pre-vaccination peak; and is one of the highest new Covid infection rates in the world. The following graph from the Israeli Ministry of Health illustrates how 2 shots of the Pfizer vaccine is providing very little protection against infection from the Delta variant.
The ineffectiveness of two Pfizer vaccine shots to prevent new infection has been attributed to the fast waning immunity of mRNA vaccines. A less discussed, but possibly more significant issue, is the growing gap between any vaccine based only on the Spike protein of the original Chinese virus, compared with the latest mutations of the whole virus as seen in the Delta, and some other variants e.g. Lambda. Albert Bourla, CEO of Pfizer, said on Fox News this week that he expected Covid variants to emerge which would completely evade current Covid vaccines.
Israel has now provided 1.5 million Pfizer vaccine booster shots (3rd dose) in three weeks, covering 60% of the population above 60, and has lowered the age for a booster to 30 for the general public, and no age limit for special groups e.g. teachers, healthcare workers etc.
On a positive note, the Israeli data appears to show that the rate of severe Covid illness e.g. hospitalisation or death, is 80%-90% lower among fully vaccinated than unvaccinated parties (unless the unvaccinated party had recovered from Covid - see below). Similar data has been seen in Los Angeles County. As of yesterday Israel had 361 seriously ill patients who had been fully vaccinated, and 330 who were unvaccinated; 5.5m eligible people are fully vaccinated. Whereas 1.1m eligible people are unvaccinated. This translates to about an 80% protection rate from serious illness for vaccinated individuals.

PROTECTION BY VACCINES - is anything better than mRNA?

A substantial amount of research suggests that a second or third shot of a DIFFERENT type of vaccine appears to provide greater protection than more shots of the same. This finding however appears to have been ignored in both the Israeli and US booster shot decisions.
Oxford University has issued a research report which indicates, based on antibodies, that the immunity generated by the AstraZeneca 'Oxford' Adenovirus vaccine, while initially much lower than mRNA vaccines, declines more slowly, such that they might provide equal antibodies at about 5 months from vaccination.
There are major unknowns as to what will create longer term immunity against Covid e.g. the reaction of T-cells and memory B cells, as compared with short term antibody production.
Questions have been asked about the relative importance of the different types of antigens generated e.g. IgG antigens in the serum, as opposed to IgA antibodies in the nasal mucus.
More broadly there is a scientific question whether a whole virion (e.g. Whole Inactivated Virus) vaccine will provide greater protection against mutations over time as there are significantly more epitopes (unique parts of the virus) for the immune system to recognize as compared to the small number of epitopes on the Spike protein, which have undergone the greatest number of mutations (e.g. Delta)..
Allied to this is the question as to the role of the Nucleocapsid ('N-protein') in providing long term immunity, including against further variants, and even against other Coronaviruses. Data seems to support a critical role for this protein in generating a robust long lasting immune response. A WIV vaccine contains both the spike and the nucleocapsid, as well as many other antigens, which may be critical to the generation of a long term robust immune response.
Data from countries which have predominantly used WIV vaccines supports the hypothesis that the whole virion is more protective against Delta than vaccines based only on Wuhan Spike protein.
The graph shown below compares 4 countries with large-scale use of WIV vaccines (Chile, Brazil, India, and Indonesia) with 3 countries relying mostly on mRNA (USA, Israel, and the UK).
The next section examines whether natural infection with the whole Covid virion is substantially protective against Delta.

Does Natural Infection provide better protection against Delta COVID than Vaccination?

Vaccines try to protect against infection by generating an immune response, as occurs after a natural infection: this can then prevent subsequent reinfection by the same disease. The latest technologies aim to create vaccines engineered to generate un-naturally high levels of short term antibodies. The critical question regarding the “new” vaccines is not their short term impact on disease but rather the protection afforded in the medium to long term against this disease and its variants.
How does this compare with immunity gained by natural infection against Covid?
BBC journalists ask the question as to whether there are marked differences in your immune system after a natural infection with coronavirus and after vaccination.
The data analysis attached at Appendix 1, based on Government data from the current Delta surge in Israel, suggests that natural infection from prior Covid provides on average 10 times GREATER protection against Delta infection as compared to two shots of the Pfizer mRNA vaccine.
The 10 times greater protection from Delta for those fully vaccinated appears to be a function of age, and increases from 4-8 times greater protection in the 20-40 age group, to 20-30 times greater protection in the over age 60 group - the most vulnerable age for serious Covid complications.

Conclusions:

Double vaccination with Pfizer’s Covid vaccine does NOT prevent most infections by Delta, although it does substantially reduce the risk of hospitalization for serious illness.
As the vaccine does not prevent infection by Delta in many cases, or its further transmission by the infected person, the concept of achieving ‘Herd Immunity’ against Delta with this vaccine is moot. Current policies are largely based on achieving herd immunity.
Recovery from a prior natural infection with Covid provides protection against the Delta variant which is 10 times more powerful than the protection provided by two shots of the current Pfizer Covid vaccine.
Vaccines based on the whole virion (Whole Inactivated Virus - WIV vaccines) are more similar to natural infection from Covid, in exposing the immune system to the whole virion, and not just to the Spike protein.
Data from countries which rely substantially on WIV vaccines are not experiencing a Delta surge comparable to those countries which have relied predominantly on Spike protein-only vaccines.

Refana believes that the above data strongly support the following hypotheses:

a whole virion (WIV) vaccine creates an immune response that is much closer to actual infection from Covid, as compared to vaccines relying solely on the Spike protein
a whole virion WIV vaccine will therefore provide significantly higher protection against the Delta surge
that any Covid vaccine modelled directly on the Delta variant will provide more protection than the SAME vaccine modelled on the much earlier Wuhan strain (i.e. all current vaccines)
that an ideal vaccine should be able to carry 'multiple payloads' as there will be further evolution of new variants, most likely continually derived from the now dominant Delta strain

Appendix

Calculation of the comparable protection against breakthrough Delta Infection: Two shots of Pfizer Covid Vaccine vs Recovery from prior natural infection with Covid.

Number of Double Vaccinated people in Israel: 5.4 million
Number of Recovered people in Israel from Natural Covid Infection: 900,000
Ratio of Double Vaccinated to Recovered: 6:1 (This is the scaling factor of 6)

All the crude data is provided in the reports of the Misrad HaBriut, the Israeli Ministry of Health
The 0-19 age group has been ignored as any age can get Covid, but only certain ages in this cohort can be vaccinated, therefore ratios in this age group are not meaningful
Column 2 shows the number of fully vaccinated persons in each age group, and total, who have had breakthrough infections since the arrival of Delta, dated from 31 May 2021
Column 3 shows the number of people who had recovered from a prior Covid infection but nevertheless got a breakthrough infection following the arrival of Delta.
Column 4 calculates the ratio of breakthrough infections in the fully vaccinated population compared to the number among people who have recovered from a prior Covid infection. This number is gross however as it does not take into account the fact that there are 6 fully vaccinated people in Israel for every 1 person who has recovered from a Covid infection.
Column 5 calculates the Relative Protection Multiple of recovery from Covid infection compared to full vaccination with two shots, scaled for direct comparability by dividing the gross ratio in Column 4 by 6.
These figures show that on average prior natural infection by Covid provides 10 times the protection against a breakthrough infection from the Delta variant than vaccination with 2 shots of Pfizer Covid vaccine.
While the average relative protection multiple is 10, the effect is highly correlated with age, whereby those over 60 enjoy 20-30 times the protective effect against a breakthrough Delta infection compared to full vaccination

Author: Brian Maccaba, CEO, Refana Inc.
Email: Brian@Refana.com Tel: +972-50-6613672

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7/29/2021

Industry Updates Volume 10

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Global Pandemic

The world will pass 200 Million confirmed cases of Covid-19 by the end of July, with an average death rate of over 2% of confirmed cases.
The ongoing pandemic is now driven by the Delta variant, ~83% of all new cases in the U.S.
Research from the UK, Israel and elsewhere are recording 'breakthrough' infections, where someone already vaccinated with e.g., two Pfizer shots, nevertheless becomes infected, and in some cases is hospitalized and dies.
- Research shows a significant drop of effectiveness of the vaccines against Delta, but a range of results, from a drop of 12% to as high as nearly 50%.
- Pfizer’s mRNA vaccine has been shown to be specifically less effective with older people.
The CDC Director warned this week that while current vaccines still protect against severe COVID-19 in a majority of cases, “We are just a few mutations away from“ a further evolution of COVID-19, which will be capable of completely evading current vaccines - all of which are based on the original Wuhan strain, and not the current prevalent variants.
- This view is shared by Prof Gupta of Cambridge University.
Some research suggests the Delta variant creates up to 1,000 times greater viral load in infected people, and this occurs rapidly in the first few days, making testing, quarantine and tracing less effective in reducing transmission.
Lancet reported a UCL study showing that the antibodies created by Pfizer and AstraZeneca vaccines start to wane after 6 weeks, and can reduce by more than 50% after 10 weeks.
Current immediate answers to this challenge range from suggesting a third shot of an existing vaccine (e.g., 3rd Pfizer shot in Israel), to mixing different types of vaccines, which has been shown to generate a better immune response than more shots of the same.
Long term solutions will likely be vaccines that will protect against Delta, future variants.

Vaccinations

While Delta is a serious concern even in countries with high vaccination rates, it is absolutely devastating in less vaccinated populations.
Although almost 4 billion vaccines have now been administered, the 'Vaccination Gap' has become ever wider. The world is now clearly split into 4 categories with respect to vaccination rates:
- 'RICH COUNTRIES' and CHINA: 54-64%; e.g., Canada 64%; UK 63%; Israel 61%; China 56%; EU 55%; USA 54%; also UAE 77% and surprisingly, Chile 56%.
  - There are a few 'laggards' in the rich countries, e.g., Saudi Arabia 37%; Japan 33%; South Korea 24%; Australia 22%.
- 'MIDDLE INCOME': 19%-33%; e.g., Brazil 33%; Argentina 33%; Morocco 31%; Columbia 25%; Mexico 24%; Russia 19%.
- 'FASTER LOWER INCOME’: 6-16%; e.g., India 16%; Indonesia 12%; Thailand 12%; Ukraine 8%; Philippines 8%; South Africa 7%; Pakistan 6%; Iran 6%.
- 'SLOW LOW INCOME': 1-3% e.g., Egypt 3%; Vietnam 3%; Bangladesh 3%; Angola 3%; Iraq 2%; Kenya 2%; Ghana 2%; Nigeria 1%; Ethiopia 1%; Algeria 0.1%.
A unique risk of the "Pandemic of the Unvaccinated" exists in the U.S., given large geographical areas comprising almost one-third of the country with vaccination rates below 30%.
- U.S. new cases/day have increased 5X in the past month; now @ 57,000 per day.

Industry

Market leader Pfizer, has recommended "more of the same" i.e., a 3rd shot of Pfizer to offset declining antibody levels; logic being that sufficiently high levels will largely protect against Delta.
- The profitability of selling 'more of the same' greatly exceeds the costs and potential loss of momentum of developing a new vaccine and going back through approvals.
- They recently raised their annual sales forecast by almost a third to $33 Billion
As expected from a commercial perspective, everyone else, except Pfizer, is emphasizing how the research shows better antibody response from mixing the types of vaccine so the second or third shot should NOT be the same as the first/second shot!
- This implies that everyone who got Pfizer shots should now get something else!
The 'something else' logic however does not help Moderna commercially, because it is too similar to Pfizer to be used as a different vaccine.
Moderna announced they are working on new vaccines more targeted to the latest variants.
Medically, there is no doubt that the best way to tackle the Delta challenge is a vaccine designed specifically to prevent Delta.
Sinovac has signed long-term agreements with UNICEF and Covax for an estimated 380 Million doses of CoronaVac WIV vaccine.

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6/30/2021

Assessment of Approved COVID-19 Vaccines

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Given the broad and extensive coverage by the media and the scientific literature on how the Pharma/Biotech world is doing in the development and deployment of COVID-19 Vaccines in 2020-2021, Refana decided to take an objective, systematic look at the 'current state' of the approved COVID-19 vaccine world, to assess how these vaccines were doing in the fight against the COVID-19 Pandemic. As a result, this 'White Paper' addresses six key questions:

How are the currently approved COVID-19 vaccines doing overall in the fight against the Pandemic?
How are they doing against the emerging 'Variants of Concern' (Alpha - UK, Beta - South Africa, Gamma - Brazil and Delta - India) vs. the original Wuhan virus?
What are the key side-effects of each approved COVID-19 vaccine
How well are the approved COVID-19 vaccines doing as far as levels and lengths of immunity and the need for further Booster shots?
How have these vaccine manufacturers' done as they transitioned from development to production of their vaccines?
How have other factors - Government-driven vaccine diplomacy, vaccine hoarding/equity issues, and vaccine hesitancy - impacted the roll-out of these approved Vaccines?

Refana summarized its findings in a short-form outline style to make these insights more accessible. Refana have also provided detailed Appendices with more specific info to support the summary outline, plus a detailed listing of all source links to the original articles and research papers that drove the assessment.

This material is not meant to be a detailed scientific review of the approved vaccines, but more of a summary of the ongoing findings related to the approved vaccines with respect to these six key questions, based on the substantial amount of reporting that has been published world-wide during the COVID-19 Pandemic. As such - and as an objective assessment of where things stand - Refana believes this material represents a good consolidated reference document on the current 'State of the Art' for the approved COVID-19 vaccines.

Since this is a highly dynamic situation, Refana is referring to this White Paper as the June 2021 Release V1.0. Refana intends to regularly update this material with the latest info on all approved COVID-19 vaccines on a periodic basis.

Access White Paper

Since this is a highly dynamic situation, Refana is referring to this White Paper as the June 2021 Release V1.0. Refana intends to regularly update this material with the latest info on all approved COVID-19 vaccines on a periodic basis.

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6/29/2021

Industry Updates Volume 9

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Global Pandemic

Globally, the pandemic shows no sign of abating as global deaths reach 4 million
The majority of COVID-19 related deaths have occurred in the past 6 months
- World-wide COVID-19 death toll in first 6 months of 2021 exceeds total COVID-19 deaths in 2020
- U.S. passed 600,000 deaths in mid-June
- Fears that the pandemic in India is spreading to neighbouring countries
- Brazil passed 500,000 deaths; with severe outbreaks in other Latin American countries, e.g., Columbia, at 100,000 deaths
- New COVID-19 hot spots have also broken out, for example in Kenya in East Africa
The ‘common theme’ across these outbreaks and hot spots is the Delta variant, which originated in India; the prediction that "No One Will Be Safe, Until Everyone Is Safe" is becoming reality
- Delta making substantial inroads, in countries: 1) WIth high vaccination rates (e.g., Israel, the UK); 2) With strong isolation/tracing (e.g., Australia) and 3) Where prior variants dominated (e.g., South Africa, with the Beta variant)
- Delta variant represents 99% of new infections in the UK and is predicted to reach 90% of all infections in Europe by August
- Former U.S. FDA Commissioner - now a Director at Pfizer - Dr. Scott Gottlieb predicted that U.S. is two months behind the UK in the penetration of the Delta variant - and to expect local mini-Pandemics in locales in the U.S. with low vaccination rates (482 U.S. counties have vaccination rates < 25%)
- The CDC Director pleaded for people to get vaccinated to prevent “Completely avoidable deaths”
Over 3 Billion vaccine doses administered to date - 40% of those are in China
- China represents ½ of the 43 Million doses currently being administered per day and 5 countries (China, India, U.S., UK, Brazil) plus the EU accounts for 80% of vaccines administered so far
The recent G-7 summit started positively, with President Biden's commitment to provide 500 Million doses of the Pfizer-BioNTech vaccine to lower-income countries, and the expectations of total pledges of 1 Billion doses from all the G7 nations
- Final communique referenced 870 Million doses
- Duke University reported a real 'new commitment' of only 648 Million doses, when prior, recycled pledges and existing EU schemes were discounted
- Duke forecasts that it will take well into 2023 to reach even 60% of the target global population globally vs. the 70% considered to be the minimum to be effective.

Industry

Pfizer-BioNTech and Moderna maintain their market leadership in the West, but there is a loss of lustre to their crown, for several reasons;
- As new variants diverge further from the original Wuhan strain - which existing vaccines are based on - the amount of antibodies generated in defense by these vaccines falls by up to 80%
- In Israel, there have been reports of people fully-vaccinated with two doses of Pfizer becoming infected; Israel has re-introduced mask-wearing and extended its travel ban for a further month
- The side effect of heart myocarditis, caused by the mRNA vaccines in a small percentage of healthy, mostly young males, has been confirmed by the CDC, in more than 300 cases in the U.S.
On the positive side, this heart side-effect is not as life threatening as the blood clots caused by AstraZeneca and Johnson & Johnson, and also affects a lower percentage
President Biden chose to provide Pfizer-BioNTech vaccine in the 500 Million dose donation
- Made it clear that this was an entirely new vaccine order vs. using up substantial pre-paid inventories of AstraZeneca and Johnson & Johnson doses under Operation Warp Speed
- Perhaps to prevent any allegation that the U.S. passed off 'inferior products' on the 3rd World
Meanwhile, potential challenges to Pfizer/Moderna's leadership position in mRNA from German start-up CureVac receded, given that the CureVac mRNA trial failed to reach the minimum 50% efficacy hurdle
- The EU and Germany had already partially pre-paid for 200 Million doses of the CureVac vaccine
Outside of Europe and North America, the WIV vaccines dominate the market overall, with close to 80% of actual vaccinations in China, India and 70 other countries (Exhibit 1 below)
Bloomberg recognized this global WIV vaccine leadership position, given the volume of inoculations and number of countries involved with the Chinese Sinovac/Sinopharm vaccines, described as "good enough"
The Brazilian regulator failed both the Sputnik and Bharat vaccines after manufacturing site inspections
FDA has ordered the destruction overall of 60-70 Millions doses of both AstraZeneca and Johnson and Johnson vaccines in its ongoing review of troubled Baltimore Production Factory, Emergent BioSolutions
Novavax announced Trial results of up to 91% efficacy (and as low as 60%, based on other calculations)
- They delayed their FDA submission by 3 months to September
- Meanwhile, The Serum Institute of India (SII) announced they will begin manufacturing the vaccine.

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5/31/2021

Industry Updates - Volume 8

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Global Pandemic

2020 warnings said that the ‘cornering’ of the vaccine market by the richest western nations would lead to a bifurcated world. A year later, that world has emerged: The pandemic rages on and more mutations appear. The West is healing, while lower and middle income countries are still in deep despair.
The U.S. passed the 50% vaccination rate - 50.3% w/ at least one dose by end-of-May. Vaccination rates have slowed considerably. Peak was 4.2 Million shots/day - now down to 1.3 Million/day in a matter of weeks. Current rate would take 5 more months to reach 75% of the target population.
U.S. Consumer research suggests that core Anti-Vaxxer segment may be as low as 18%, leading to an increase of incentive 'nudge economics" to encourage vaccination, including free participation in lotteries, discounts on supermarket shopping, free Uber and Lyft rides to get a vaccine - paid for by the White House - walk-in vaccinations at sporting events, e.g., at four locations at the Indy 500 auto race.
70 Million unused vaccines exist within the U.S. distribution system, allowing same day, no appointment, walk-in vaccination, and even choice of vaccine, in much of the U.S..
Many other major western countries are catching up (France 36%, Germany 43%) and a few are ahead (UK 58%, Canada 55%, Chile 54%, Hungary 52%).
For advanced economies in the West, the pandemic is seen as coming under control, and attention is shifting to: 1) Incentives needed to get close to herd immunity, (at least 70%); 2) How long does immunity last; and 3) Combating dangerous new variants. In the UK and France, a 3rd round of shots has already been arranged, with longer term plans for annual boosters for the next 3 to 5 years.
Some advanced economies have lagged behind: Australia 14%; South Korea 9%; Japan 6%. In Australia the Qantas airline is offering unlimited flights for a year incentive to support the vaccine push.
Rest of the world? Global cases now exceed 171 Million with over 3.6 Million deaths officially reported.
85% of the 1.91 Billion vaccine shots administered have been in upper income countries, but only 0.3% of shots in low-income countries. Of the daily global vaccination rate of 34 Million per day, 25 Million are taking place in China, USA, EU and UK. This leaves just 9 Million per day for the "other 5 Billion people".
India with a population of nearly 1.4 Billion, and a large domestic vaccine manufacturing industry, is achieving just 2.5 Million vaccinations a day, allowing the pandemic to continue to spread, and leading to somewhere between 4,000 (official) and 20,000 (unofficial estimates) deaths per day.
Refana has modeled vaccine availability/administration for the remaining 3.5 Billion people - 5 billion less India, 45% of the world's population - forecasts 5 years to achieve a 70% vaccination rate globally.

The Business of Vaccines

The WHO has now approved two Whole Inactivated Virus Vaccines (WIV) for Emergency Use Access, Siopharm and now Sinovac, both produced in China.
Airfinity market study reports that 2021 would see between $115-$190 Billion of actual vaccine sales this year, almost equalling the entire previous 5 year market forecast of $157 Billion for 2021-2025. These figures represent potential given reported orders, but may be constrained given production constraints.
A significant factor in these large market values is that vaccine pricing is at a level 300% higher than prior earlier forecasts, as the enormous value of Covid vaccines, even at these prices, is being clearly recognized compared to the human and economic costs of the pandemic.
The big winners forecast by Airfinity for 2021 revenue are Pfizer-BioNTech at $44 Billion, Moderna at $32 Billion, Sinovac at $25 Billion and Sinopharm at $23 Billion.

Medical/ Vaccine Updates

SARS-CoV-2 is mutating at an alarming rate. New mutations are progressively more virulent, with increased capacity to both infect and cause more severe illness.
While single “epitope” vaccines (e.g. Pfizer, Moderna, Novovax, J&J) continue to show efficacy against new variants, the efficacy/ protection of these vaccines is significantly reduced.
Given > 50% vaccination of populations in wealthy countries, new variants are unlikely to spread in those countries. Even with reduced efficacy, vaccines still slow the spread significantly: “Shifting the curve”
BUT, given epidemiological considerations of variant spread, less vaccinated 2nd/3rd world countries will need to utilize new vaccines effective against the new variants, to significantly reduce disease spread.
Recent analysis shows that in 18-36 months, new variants of SARS-CoV-2 may have mutated sufficiently to enable reinfection in populations vaccinated with existing vaccines for the earlier variants. To prevent this outcome, the reservoir of new variants from the unvaccinated poorer populations will have to be eliminated through broad and comprehensive vaccination programs.

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4/9/2021

Industry Updates - Volume 7

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There is a media debate as to whether the pandemic is stabilizing, or whether we are entering a dangerous new 3rd and 4th wave, driven by toxic new mutations to the virus, such as the UK, South African, and Brazilian variants. Refana's view is as follows:

Global Pandemic

Total deaths attributed to Covid-19 worldwide have just reached 3 million (Bloomberg). While this is a horrific total, the death rate globally may have begun to plateau.
It took approximately 9 months to the end of September for the first 1 million deaths to occur, but just 3.5 months to mid-January for the 2nd million; and almost the same period again (just under 3 months to the first week of April) for the 3rd million.
There is clear evidence from Israel, the UK, and early indications in the US, that the vaccine campaigns are working; even as cases continue to rise significantly in a number of US states.
Israel has successfully implemented a major 're-opening' of the economy and large scale social and cultural events, utilising a 'digital passport' for vaccinated people.
The EU is lagging due to its vaccine supply and logistical issues (vaccination coverage rate of just 9% in the EU so far compared to approx 26% in UK and US, and over 50% in Israel) but this is expected to be resolved by the second half of the year. Major new lockdowns are being implemented in a number of leading countries, including France and Canada.
Worldwide we are getting close to where 5% of the population has now had one vaccine. The current rate of 16 million shots per day could cover the globe, on a two shot regime, in about 800 days. But in practice this will likely take longer, as over 70% of the current vaccinations are in just 3 large countries, China (5 million per day), India and the USA (>3 million per day each and rising).
The Refana view is that the Pandemic will switch to Endemic status in the advanced countries, once enough vaccinations have occurred; and the focus in these countries will be on dealing with new variants and booster shots from the end of 2021. But in less developed regions, the Pandemic is likely to continue for the next 24 months, before turning to Endemic status everywhere.
In Brazil the pandemic seems to be getting out of control with hospitals overwhelmed, dangerous new variants emerging, inadequate supply of vaccines and over 4,000 deaths per day.
In India the situation in a number of states in India is also extremely severe. The Indian government has banned the export of any vaccines manufactured in India until July, which will have a serious impact on many other lower income countries.

Industry and Economics

Pfizer/BioNTech and Moderna have become the clear market leaders, especially in the advanced economies.
AstraZeneca continues to struggle, most recently in a link established by the European Medicines Agency between the vaccine and a rare form of blood clot, that has particularly affected younger to middle aged females. While the risk is perhaps only 1/100,000 overall it may actually be 1/25,000 in the highest risk groups. Conversely the risk of death from the Coronavirus in developed economies for females aged 18 to 50 is no more than 1/20,000. Of 69 recorded cases in the EU today there have been 23 deaths. Multiple countries have now restricted the use of the AstraZeneca vaccine.
For lesser developed countries the World Health Organization (WHO) continues to recommend AstraZeneca, but this may change as a number of African countries have announced that they will refuse to accept this vaccine. It is currently not clear whether or not AstraZeneca will continue to seek EUA from the FDA in the United States. Despite earlier announcements, no date has been set for the hearing. Meanwhile the SAGE committee of the WHO is currently reviewing the Whole Inactivated Virus vaccines from Sinopharm and Sinovac, and is likely to grant them EUA status during April.
A small number of cases similar to the AstraZeneca blood clots have been attributed to the Johnson & Johnson vaccine. If this problem applies to Johnson & Johnson as well as AstraZeneca it may be an intrinsic problem of all Adenovirus vaccines, which includes the Chinese Cansino and Russian Sputnik V.
In the EU significant quantities of Pfizer and Moderna are to be delivered in the coming months which will be urgently needed if AstraZeneca and possibly Johnson & Johnson will no longer be widely used.
Russia's efforts to promote the Sputnik vaccine in Europe are running into controversy. The Prime Minister of Slovakia lost his position after the batch of Sputnik Vaccines he purchased from Russia, were found to be different to the one reviewed in The Lancet. The EMA has requested data which has not been provided. There is also a complaint that the data used in early testing did not meet ethical guidelines. The Russian Direct Investment Fund has just signed contracts with 6 Indian firms to manufacture the Sputnik Vaccines to GMP quality standard (following manufacturing problems in Russia).
The UAE has concluded a deal with Sinopharm for technology transfer to support manufacture of this WIV vaccine by a UAE company, Group 42.
Bharat's US partner Ocugen says they will be submitting their WIV vaccine to the FDA for EUA.
Valneva is commencing a Stage 3 trial of its WIV vaccine in the UK, having issued a press release of positive Stage 2 results.
Johnson & Johnson got off to a slow start after obtaining EUA due to production issues which spoiled 15 million doses in the U.S. The New York Times reported that a further 64 million doses may have also been contaminated.

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3/10/2021

Industry Updates - Volume 6

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March has seen warnings of a 4th Wave, emergency use approval for a 1-shot vaccine and an increase in vaccine sales. Volume 6 looks at these headlines and more.

Global Pandemic

Global caseload up to almost 120 Million cases, 2.6 Million deaths
World Health Organization and CDC in U.S. issued warnings for a '4th Wave' of Covid-19 cases, triggered by more contagious COVID-19 variants from UK, South Africa, Brasil, elsewhere
However, the overall trend in new infections/deaths has been trending downwards in many countries for almost two months
U.S. situation is complex - 20+ states have seen increases in infections in recent weeks, even as a number of states - led by 2nd most populous state Texas (29 million people) - cancelled mask mandates and are opening up
Vaccination programs in two major countries - U.S. and the UK - have significant momentum
- U.S. now at 2+ million vaccinations/day; Biden administration projects there will be sufficient vaccines for everyone who wants to take them by May
- 312 Million vaccinations world-wide
- 2/3rds of all doses have been administered in U.S., UK, China, EU Countries
- 100 countries still without any vaccinations
Israel reached vaccine doses administered of 7.5 Million, compared with its population aged 15 or older of 6.7 Million
- Covid infections in the 50+ age group have fallen from 25% to 11% of new infections, while 47% are in the 19 or younger age group
- Israel re-opening large venues (e.g., sports stadiums, concert halls) allowing access to Green digital passport holders which attest to full vaccination or antibodies from prior infection
- Fears however as to the risks from the South African variant which has arrived; and the ‘R Rate’ still stubbornly close to 1, vs. 0.5-0.7 if the Pandemic is subsiding.

Industry

Johnsons & Johnson (J&J) one-shot vaccine was given EUA on 28 February
- U.S. efficacy of 72% (but lower elsewhere, presumably due to new COVID-19 variants) compared to 94% for the mRNA competitors
- Leading officials - including Dr, Fauci and the acting FDA Commissioner Janet Woodcock - stated that there is no real difference between these vaccines w.r.t. to serious outcomes
- People should simply take whatever they can get
- White House brokered deal between rivals Merck, J&J to increase production of J&J’s vaccine
Research shows that Pfizer vaccine produced 67% less antibodies against the South African variant; and Moderna produced 83% less antibodies
- Implications for protection not clear; both companies are working on new vaccines (or booster shots for those previously inoculated) against South African variant
AstraZeneca expected to announce shortly that it has achieved enough events in its Stage 3 American trial to read data and make application to the FDA for EUA
The European Medicines Agency (EMA) has commenced a review of the Russian Sputnik V vaccine; officials cautioned that they have not received the data required on vaccinated people
- Surveys in Russia found that 60% of Russians did not trust the Sputnik vaccine
The Chairman of Sinopharm - which has previously announced 79% efficacy for their WIV vaccine - said it was effective against new variants, including the South African variant
Reuters reported that Sinovac was effective against the Brazilian variant
Sinovac announced an updated efficacy rate from its Turkish trial of 83.5%
- Mexico, Thailand, The Philippines, and Hong Kong have approved Sinovac’s WIV vaccine
- Meanwhile, Ukraine fined local distributor of Sinovac for failing to deliver the vaccine on time
In India, Bharat announced Stage 3 results of its WIV vaccine, showing 81% efficacy
The WHO has granted EUA to Pfizer, Moderna, and AstraZeneca and will review next Sinopharm, Sinovac and J&J.

Financial news

Bharat sold 20 Million doses of its WIV vaccine to Brazil for U.S. $290 Million ($14.50/shot), even before it had its Stage 3 trial results
- Mexico on the verge of approving Bharat’s vaccine
AstraZeneca sold its stake in Moderna for approx U.S. $1 Billion, but has not disclosed when this occurred; current market value of the stake would be close to U.S. $4 Billion
Moderna is forecasting Covid-19 vaccine sales of U.S. $18.4 Billion this year; compares with total sales revenue for all products at AstraZeneca last year of U.S. $26 Billion
Pfizer is projecting U.S. $15 Billion in Covid-19 vaccine sales this year
J&J expected COVID-19 vaccine sales this year: Up to U.S. $10 Billion
AstraZeneca expected COVID-19 sales this year: U.S. $6.4 Billion
Other players - Sinovac, Gamaleya, Novavax - all expecting U.S. $ Billions in sales
Average price points across existing suppliers: U.S. $20 - U.S. $40 for two-dose shots
G7 pledged U.S. $4.7 Billion to help finance global equitable access to tests, treatments and vaccines; compares with the U.S. $22 Billion estimated that is needed just to vaccinate the world's poorer countries.