Prof. Justing Stebbing a Book: Witness to Covid 2020

Prof. Justing Stebbing a Book: Witness to Covid 2020

As more than 5 million people according to Hopkins are confirmed to have died from Covid globally, infection levels rose last week in most European countries with an accompanying rise in hospitalisations, continuing to suggest that Europe is in the early stages of a fourth wave. But, cases in the UK fell by 13% due to the half-term holiday, although some still caution that the break may not be long enough and the booster rollout not sufficiently quick to prevent the need for plan B (mask wearing and working from home) before Christmas. Nevertheless, Boris Johnson reiterated that the UK will have a Christmas without restrictions, saying he sees “no evidence whatever” in favour of a renewed lockdown or tighter measures.

Supporting the case for boosters, Israel has now administered booster shots to ~67% of its adult population and saw a 36% decline in cases last week and a 30% fall in new severe hospital admissions, the fifth week of decline on both metrics.

Shameless plug now, my book on COVID is out on Amazon, ‘Witness to COVID, 2020’, which when unsigned is very rare and valuable:

After a summer of reports of breakthrough infections, when it seemed that everyone knew someone who tested positive after vaccination, recently released CDC data sheds light on how common these cases really were, how severe they became and who was most at risk:

Compared with the unvaccinated, fully vaccinated people overall had a much lower chance of testing positive for the virus or dying from it, even through the summer’s Delta surge and the relaxation of pandemic restrictions in many parts of the country. But the data indicates that immunity against infection may be slowly waning for vaccinated people, even as the vaccines continue to be strongly protective against severe illness and death. “The No. 1 take-home message is that these vaccines are still working,” said Dr. David Dowdy, an epidemiologist at the Johns Hopkins Bloomberg School of Public Health. “If you saw these data for any disease other than Covid, what everyone’s eyes would be drawn to is the difference between the unvaccinated and fully vaccinated lines.” The data shows notable differences in breakthrough death rates by age and slight differences in both case and death rates by vaccine brand.

The CDC data is based on health department records from 14 states and two cities. A second dashboard reveals similar trends for hospitalized patients with and without vaccination. All vaccinated age groups saw similar rates of breakthrough infection, and they all had much lower rates of infection and death compared with their unvaccinated peers.

While every age group had similar rates of breakthrough cases, death rates varied more drastically by age. Unvaccinated seniors were the most likely to die from Covid of any group. Still, vaccinated people 80 and older had higher death rates than unvaccinated people under 50. “Age is our top risk factor for vaccine breakthrough deaths,” said Theresa Sokol, the state epidemiologist in Louisiana.

Breakthrough deaths among seniors may be because of immunosenescence, or the weakening of the immune system in older people, said Heather Scobie, an epidemiologist at the C.D.C. who helps lead the team that produced the new data. “They don’t usually form as robust a response to vaccination,” added Dr. Scobie. “Hopefully the booster dose for ages 65 years and older will address that issue.” The federal data also makes it clear that all three brands of vaccine administered in the US substantially reduced rates of cases and deaths. But among those vaccinated, Johnson & Johnson recipients had slightly higher rates of breakthrough cases and related deaths. And Pfizer-BioNTech recipients had slightly higher rates than those who got Moderna.

Similar data from scientific studies helped shape the new federal recommendation that all J&J recipients, 18 and older, receive a booster dose at least two months after getting the first shot, said Dr. Scobie. In contrast, booster shot recommendations for those who got the Pfizer or Moderna vaccine are focused on high-risk groups, including those over 65, and younger adults at greater risk of severe Covid-19 because of medical conditions or where they work.

The CDC data, which will be updated monthly, is the closest yet to a detailed, nationally representative view of breakthrough cases and deaths. States are not required to report this information, though many do in myriad formats, and the CDC had previously only provided estimates of total breakthrough hospitalizations and deaths. The data can also give scientists a crude understanding of the effectiveness of vaccines over time. If the ratio of cases or deaths among the unvaccinated to those among the vaccinated holds steady, the vaccines are thought to be maintaining their protection.

For example, the ratio of case rates declined somewhat in the summer, to six times as high for the unvaccinated in August from about 11 times as high in mid-June, giving scientists reason to believe that the vaccine’s protection against infection might be waning slightly. The ratio for deaths has been flatter over time for all but the oldest age groups, an indication that vaccine protection against death is holding strong.

The C.D.C. data so far runs through early September and captures only the crest of the Delta wave. But data from states like NY/California shows similar patterns through September and October. That suggests that the vaccines, despite some slight differences among the brands, are still working to protect against the most severe outcomes.

Next, how bad can Covid-19 be for people with cancer? A new study that combed through more than 500,000 patient records concludes it depends: patients who received cancer treatment within three months of being diagnosed with Covid had a higher risk of hospitalisation, ICU admission, and death than Covid patients without cancer. After accounting for such factors as age or underlying conditions, the researchers said people with no recent cancer treatments weathered Covid just about as well or better than Covid-infected people without cancer. Among cancer patients, those with metastatic solid tumours, and especially those with blood cancers, had worse outcomes. And the kind of recent cancer therapy mattered: chemotherapy and chemoimmunotherapy were associated with worse outcomes:

In March 2021 drug manufacturers predicted that 12 billion doses of covid-19 vaccine, enough to fully immunise at least 70% of the world’s population, could be manufactured by the end of the year. That assessment was confirmed in September in a report by the International Federation of Pharmaceutical Manufacturers and Associations, though it also warned that “most doses in the production queue are already allocated” to high income countries. And this report states that many were waiting for Novovax for the developing world, but no surprises they’re beset with manufacturing issues:

Moderna announced an agreement with Gavi, the Vaccine Alliance to supply up 116.5 million doses of vaccine to be delivered in the second quarter of 2022. The exercise of these options for additional doses represents an increase from an earlier agreement for 60 million doses of Moderna’s COVID-19 vaccine that was communicated earlier this year. As per the advance purchase agreement signed on behalf of the COVAX Facility, Gavi continues to retain the option to procure 233 million additional doses in 2022 for a potential total of 500 million doses between 2021 and 2022 under the agreement. All doses are offered at Moderna’s lowest tiered price. This agreement covers the 92 Gavi COVAX Advance Market Commitment (AMC) low- and middle-income countries. COVAX is a global initiative co-led by Gavi, the Vaccine Alliance (Gavi), the Coalition for Epidemic Preparedness Innovations (CEPI) and the WHO, to ensure equitable access to COVID-19 vaccines for all countries, regardless of income levels.

But now, only 1.5% of people in low-income countries have received their jabs. Seventy countries have yet to vaccinate 10% of their populations, and 30 countries, including much of Africa, have vaccinated fewer than 2%. In Latin America, only one in four of the population has received a dose of covid vaccine. The solution widely canvassed in high income countries is redistribution. The United States, United Kingdom, European Union, and Canada could have 1.2 billion doses available for redistribution by the end of the year. A spokesman for Pfizer has told the BMJ that the company will provide one billion doses to low-and-middle-income countries in 2021 and a further billion in 2022, with “500 million doses at the not-for-profit price.” But health experts from low-and-middle-income countries remain unimpressed. They are demanding a more permanent and fundamental overhaul of vaccine production.

African leaders are also angry. “How can a continent of 1.2 billion, projected to be 2.4 billion in 30 years, where one in four people in the world will be African, continue to import 99% of its vaccines?” asked John Nkengasong, the virologist who heads the Africa Centres for Disease Control and Prevention in Addis Ababa, at a press conference in early 2021. Cyril Ramaphosa, president of South Africa, has said, “We just cannot continue to rely on vaccines that are made outside of Africa, because they never come.” But why is the manufacturing of vaccines so uneven in the first place?

Essential kit for making vaccines has been in short supply, and this has exposed how the chain is reliant on a handful of countries. The kit includes filters, plastic pipes, and most importantly the giant sterile bags needed to grow the cells for all vaccines inside large vessels called bioreactors. Bioreactor bags are mainly supplied by MilleporeSigma, now a division of German Merck, itself reliant on a web of small suppliers. Throughout 2021, extraordinary demand for these bags left vaccine manufacturers unsure whether supplies would continue “threatening global vaccines rollout.”  Each vaccine consists of up to 200 components, including niche products suddenly in demand in unprecedented quantities affecting all markets. Lipid nanoparticles, the delivery technology crucial to introducing fragile mRNA molecules to human cells, were sold in gram quantities until Spring 2020. Then they were suddenly urgently in demand by the hundreds of kilos for mRNA-based vaccines such as Pfizer-BioNtech’s. This is the total % of people who have received one dose up to October 2021.

“It was a scale-up that hadn’t been done before,” says Pieter Cullis, chair of Acuitas. Lipid nanoparticles were identified as an urgent gap in the vaccine supply chain by Biden’s administration in January 2021, his second day in office. By June, Acuitas was contracting out manufacture. Pfizer now has a five year lipid supply agreement with the London company Croda, which has quadrupled production at its UK site to meet demand. Another company, CordenPharma in the US, supplied lipid nanoparticles to Moderna for its mRNA vaccine and has announced a major expansion of its facilities in Switzerland and France as well as Colorado. None of these manufacturers are outside Europe or the US. Non-mRNA vaccines have also been affected by component issues. The Novovax vaccine uses a laboratory made version of the Sars-CoV-2 spike protein that requires a crucial ingredient, saponin, an extract of the rare Chilean soapbark tree, previously used for root beer and Slurpees. Problems in harvesting the tree might contribute to continuing repeated delays in rolling out the vaccine.

Global supplies of AstraZeneca’s covid-19 vaccine—the workhorse of the WHO led global vaccine alliance supplying the bulk of doses to low-and-middle-income countries around the world—have been hit by a shortage of serum for the vaccine. AstraZeneca has several of its own plants, as well as those of subcontractors, making serum and other components across Europe. But a plant in the Netherlands wasn’t producing enough to be included in the company’s application for approval to European regulators at the end of December 2020. An emergency import of serum from the US, more than half the amount required, according to Politico, could not prevent a knock-on effect to 2021 vaccine stocks.

Vaccine manufacturers have attempted to reduce bottlenecks by exporting to low-and-middle-income countries before the final manufacturing step: putting vaccine into vials, known as fill and finish. By March 2021, the global covid vaccine alliance Covax had drawn up a list of several hundred facilities worldwide that fill vials with injectable drugs including insulin, monoclonal antibodies, and antibiotics and could also fill and finish covid-19 vaccine vials. A more powerful practice, “local supply first”, has had a more substantial effect. The Biden administration maintained the previous policy of “America first” in regard to vaccine distribution. This policy was cited by pharmaceutical experts as the reason why Germany required its own manufacturing facilities for the Pfizer-BioNTech vaccine, approved by the European Medicines Agency on 26 March 2021. AstraZeneca, with Covax, set up licensing agreements to fill and finish its vaccine with several regional manufacturers, notably the Serum Institute in India, with an agreement to be the major supplier of vaccines to Africa. But this agreement meant nothing when India was hit by its second wave of covid-19. The Indian government blocked the export arrangement so it could keep stocks made in its borders for domestic supply, a move only recently reversed. Meanwhile 40% of 10 million doses of Johnson & Johnson vaccines, filled and finished by Aspen Pharmaceuticals in South Africa, were being sent to Europe under a “gentleman’s agreement,” while South Africa was desperate for stocks. This agreement was rescinded only after a backlash.

“Every country wants to vaccinate their own people first, indeed they have a duty to do so,” says Stephen Morris, research fellow in vaccine process analytics at University College London’s Department of Biochemical Engineering, “That inevitably means that countries with existing drug or vaccine manufacturing experience will have among the highest rates of vaccination.” In April, the African Vaccine Manufacturing Summit pledged to ramp up capacity in manufacturing vaccines to be used on the continent from 1% to 60% by 2040. An investigation found that manufacturing capacity already exists in Senegal, Tunisia, Cape Town, and Algiers, with Nigeria and Ethiopia planning to increase capacity. India and Indonesia are also making hepatitis B vaccine using recombinant protein, which is “a well-established production methodology currently in late stage clinical trials for covid-19,” says Morris.

Much has been made of intellectual property and patent issues, but more local efforts are already moving vaccine manufacture outside the US and Europe in a way that hasn’t happened before. Perhaps surprisingly, the cutting-edge mRNA vaccines are the likeliest candidates to establish new production lines in low-and-middle income countries. “Once the technology transfer has taken place, it’s possible to set up a plant for mRNA faster than for viral vector vaccines,” says Morris. With traditional vaccines, you need a big factory to make the protein or the virus, and it takes a long time to grow them.

Growing cell lines can take months, and tiny variations in the process can make all the difference to quality and yields. In February 2021, filtration problems at a plant in Seneffe, Belgium, with a contract to produce covid-19 vaccine for European countries reduced production by 75 million doses leading to a major row between AstraZeneca and the EU. The beauty of mRNA is that you don’t need to worry about that. If you inject nano-encapsulated mRNA into a person, it goes into the cells, and then the body is your factory. The body takes care of everything else from there. In July, Pfizer-BioNTech announced that it was collaborating with the South African biopharmaceutical company Biovac, with plans to produce 100 million doses of their mRNA vaccine annually from 2022 and for “all doses [to be] exclusively distributed within the 55 member states that make up the African Union.” In August, Brazilian company Eurofarma signed an agreement with Pfizer-BioNTech to part manufacture its mRNA vaccine, the companies’ first expansion into Latin America.

A Bangladeshi company, Incepta, which already produces several non-coronavirus vaccines for export, is one of several candidates to have sought licences to manufacture mRNA vaccines currently produced by Pfizer-BioNTech. “If the antigen was provided, production could start immediately, filling vials for about 500 million doses a year,” Abdul Muktadir, chair of the Incepta, told Geneva Health Files in March. So far, Pfizer has refused Incepta’s approaches. A spokesperson declined to say why when asked. Zahid Maleque, health minister for Bangladesh, has also asked AstraZeneca to provide their technology “so that we can produce the vaccine locally,” acknowledging the need to “establish required facilities and employ skilled technical [people].” To make use of such facilities would still require countries to spend hundreds of millions of dollars expanding research capacity and setting up regulatory bodies that meet international standards, as well as commitments from governments to purchase the vaccines and set up the supply chains necessary to feed manufacturing.

Back in July, the Coalition for Epidemic Preparedness Innovations (CEPI), which funds vaccine development and helped set up Covax, announced the Covax marketplace, an online innovation matching global suppliers to global vaccine manufacturers for the most critical categories, notably bioreactor bags, cell culture media, filters, lipids, vials, and stoppers. CEPI emphasises that this is a short-term objective, part of its longer term £3.5bn investment plan to enable low-and-middle-income countries to “take full ownership of their national health security.” What is needed long term, they say, is local manufacturing of components and stages in the manufacturing process to expedite access to urgently needed vaccines for populations living in locations remote from the main manufacturing plants. Jeremy Farrar, director of the Wellcome Trust, one of CEPI’s funders, said in February that “local access may depend on having more local manufacturing hubs, not only for vaccines but also essentials like dexamethasone and [personal protective equipment], down to the vials that you put vaccines into.” He added, “This may create opportunities, as well. Countries with small populations but good manufacturing capacity will have opportunities in global as well as domestic supply: Singapore, Denmark, Senegal, or Ecuador, for example.”

The International Federation of Pharmaceutical Manufacturers and Associations says that the drug industry’s current production rate of 1.5 billion doses per month means that over 24 billion doses of covid vaccines could be produced by June 2022. Ensuring they are made where they are needed is the next challenge.

Overall, last week's data shows cases are continuing to rise across much of Europe, which is being accompanied by a rise in hospitalisations as well. This in contrast to the US and Israel which are seeing cases and hospitalisations fall. Therefore, the data continues to suggest that Europe is in the early stages of the 4th wave.

Development in UK infections & hospitalisations:

Over the week October 25 – October 31 the new infection count fell by 13% to 281,940, with the fall likely entirely due to reduced testing during half-term (as testing levels also fell 13% and the rate of positive tests was relatively flat at 4.7% (prev. 4.9%)). Per day infections were between 36,294 and 43,349 (prev. week between 39,962 and 51,412). We would expect cases to continue to fall for the next few weeks as well following half-term. Hospitalisations were flat w-o-w at c. 6,986 or still 1,000 per day (based on the first 3 days of the week) with the rate of hospitalisations at 2.5% (prior week 2.2%). The occupancy of ventilators increased by 8% this week to c. 20.9% (last week 19.4%), which equates to c. 939 people. If hospitalisations rise from here to reach 10,000 a week, then plan B could be back on the table with a return to mask-wearing and potentially working from home. The booster vaccination program should help curb hospitalisations, but the rollout still seems slow.

Although cases fell significantly this week in children due to the school holidays they didn’t fall in the above 65s and hence hospitalisations didn’t fall this week. We hope cases continue to fall after half-term with the rollout of the vaccine in the 12-15 year olds and the provision of more booster shots. However, given there was only a small fall in cases this week and half-term is over it is possible that infections and hopsitalisations will resume growth in the next few weeks such that plan B (reintroduction of face coverings and working from home) could be required before the Christmas holidays are reached.

Development in Vaccinations in the EU5, Israel & the US

The UK has partially vaccinated c. 92.3% of its adult population, with a total of c. 50m first doses administered, representing 73.4% of the UK population or 86.9% of the vaccine-eligible 12+ population (prev. week 86.5%). Full immunisation has now been achieved in 86.5% of adults, with a total of 45.7m doses administered to date, covering 67.1% of the total population or 79.5% of the vaccine-eligible 12+ population (prev. week: 79.2%). The vaccination rate for the primary series declined by 10% this week to an average of 60k doses per day, with first doses averaging 38k doses per day and second doses averaging 22k doses.

Looking at vaccination by age, we estimate 37% of the 12-17 age group have received at least one dose (prior week: 37%). This compares with 74% of 18-24 year olds (prior week: 74%), 75% of 25-29 year olds and 95% of those aged 30 and over. Full immunisation has been achieved in 63% of 18-24 year olds (63% in the prior week), 67% of 25-29 year olds (67% in the prior week) and 76% of 30-34 year olds (76% in the prior week) compared with 93% in the 35+ population. The UK has administered 7.9m booster doses (prev. week 6m), with an estimated c. 45% of over 65s covered with a booster dose (prev. week: 34%).

Looking across the EU4 on the primary vaccination series, Spain has partially vaccinated 91.2% of its adult population, France is at 90%, Italy is on 83.0% and Germany is on 80.2%. Full vaccinations are 89.6% for Spain, 88.0% for France, 79.8% for Italy and 77.3% for Germany. On the rollout of booster jabs, Germany has administered 1.9m booster doses to date (prev. week: 1.5m), France has administered 2.9m doses to date (prev. week: 2.3m), Italy has administered 1.6m doses (prev. week: 1m) and Spain has administered 962k doses (prev. week: 465k), having started its rollout in over 70s this week.

The US has partially vaccinated 206m adults (205m in the prior week) i.e. 79.8% of the adult population. Full immunisation has been achieved in 68.5% of adults (68.9% in the prior week). A total of 17.7m people have now received a booster dose (prior week: 12.5m), with 10.9m doses administered to those over 65, representing 23.3% of the over 65 population.

Israel has now partially vaccinated 71.4% of its total population and has fully vaccinated 65.6% of its population. Booster doses have been administered to 45.2% of the total population and 67% of the adult population (prior week: 66%).

Source: CDC, UK, French, Germany, Spain, Italy governments. *Note, Germany data is based on reported vaccination data. This week, Robert Koch Institute and the German Health Ministry announced that there has been underreporting in the Germany vaccination rates with an estimated 84% of adults partially vaccinated and 80% fully vaccinated (based on survey data).

Examining the impact of the Vaccine in the UK, US and Israel:

Israel, which has fully vaccinated c. 90% of its adult population and has administered booster shots to c. 67% of its adult population, saw a 36% decline in cases this week, with new severely admissions down 30%, the fifth week in a row we have seen a decline on both metrics. Specifically, cases this week averaged 631 per day while new severely ill admissions averaged 2 per day, the lowest level since July 17th. Focus remains on the durability of protection from the booster doses, particularly against emerging strains, with the Delta Plus AY.4.2 identified in a patient in Israel for the first time this week.

In the US, daily cases declined by 4% to 75.9k (based on data for first 5 days), with hospitalisations down 11% to 5,149 admissions per day, a weekly level of c. 36k admissions, the sixth week in a row we have seen a decline on both metrics. There has been evidence of rising cases in certain states in the US, particularly in unvaccinated 5-11 year olds, though this should be curbed by vaccination following FDA approval of the Pfizer/BioNTech vaccine this week for use in this population.

In the UK, cases declined by 13% this week to an average of 40,277 cases per day although testing also declined 13%, with hospital admissions broadly flat at 1,084 new admissions per day (based on data for the first 3 days). The AY.4.2 Delta Plus variant was identified as a variant under investigation on October 20, 2021, now accounting for c. 10% of Delta case in the UK. AY.4.2 is currently thought to be around 10-15% more infectious than the original Delta strain. There is no evidence yet as to whether this strain causes more severe illness than Delta and on impact on vaccine efficacy against hospitalisation.

The latest data on COVID-19 hospitalisations by vaccination status as at October 28, 2021 continue to support the UK's decision for rollout of boosters in over 50s with 68% of hospitalisations (n=8,338) in over 50s. The latest data suggests the booster rollout could be extended to those over 40 given that hospitalisations in 40-49 year olds now account for 12% of all hospitalisations, compared to hospitalisations in 50-59 year olds, which account for 14% of all hospitalisations.

Vaccine efficacy, based on real-world surveillance data in the UK, shows efficacy against Delta of 65-70% for the Astra vaccine and 80-95% for the Pfizer/BioNTech and Moderna vaccines, with evidence of waning efficacy for both Astra and Pfizer/BioNTech. Effectiveness against hospitalisation from the Delta variant is over 90% for all three vaccines. Vaccine efficacy against Delta hospitalisations is estimated to wane from 86.2% to 76.3% for the Astra vaccine in over 65s, compared with 100% to 91% for the Pfizer vaccine in the same population after 5 months. This compares with 94% efficacy of the Astra vaccine in the overall 16+ population, waning to 77% after 5 months, compared with 99.7% efficacy of the Pfizer/BioNTech vaccine waning to 92.7% after 5 months. Initial odds ratio point estimates for vaccine efficacy suggest vaccines are equally as effective against cases from the AY.4.2 variant as the original Delta variant with an OR for the AstraZeneca vaccine of 1.02 (95% CI: 0.95-1.09), Pfizer/BioNTech of 1.08 (95% CI: 1.00-1.16) and Moderna of 0.96 (95% CI: 0.69-1.35). Putting this into perspective, an OR > 1 would suggest lower vaccine effectiveness compared to Delta, with an OR of 1.12 suggesting a modest reduction in vaccine effectiveness from 83% (Pfizer/BioNTech latest reported efficacy against Delta from the UK) to 81%.

Development in New Infections in the EU5:

  • Looking at the new infection data on a weekly basis over the last week (October 25 – October 31) the EU5 new infections rose by 4% to 499,045 with cases rising in 4 out of 5 countries. Cases rose in Italy by 32% to 30,779, in France by 11% to 41,009, in Spain by 1% to 13,437, in Germany by 59% to 131,880. Cases fell in the UK by 13% to 325,436 due to the half-term break.
  • Since March the death rate has fallen in most countries due to vaccinations and the fall of cases of the Alpha Variant. Death rates are higher for Germany and Italy due to the fall in testing, resulting in less diagnosis.
  • Daily Hospital Admissions: Hospital admissions in France were up 10% at 1,703 for the week ending October 31. In the UK, hospital admissions were flat at c. 6,986.
  • UK hospitalisations by Age: The data was updated on October 14, 2021 for the period up from Sept 5, 2021 to Oct 5, 2021. During September and the first 5 days of October there continued to be a rise in the proportion of people hospitalized above the age of 85. The proportion of hospitalisations from the age group 18-54 continued to fall due to uptake of vaccines. We would anticipate boosters to reverse the rise in hospitalisations in the 85+ age group in the coming weeks, with this data point out the need for boosters, particularly in this age category.


Prof. Justin Stebbing

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