Monthly medical update – Issue 7
5 March 2021
By Nicola Oliver and Dan Ryan for 
http://www.covid-arg.com
COVID-19 Actuaries Response Group – Learn. Share. Educate. Influence.
Given the pace of change with ‘all things COVID’, it can be hard – even for those who follow all the updates – to know what the overall state of play is regarding medical developments in particular, as opposed to just the most recent news. In this regular monthly medico-Bulletin, we provide a summary of what we believe the current medical position to be.
Vaccines
Current situation
12 COVID-19 vaccines that have achieved regulatory approval, details below (link):
| Developer | Type |
| Pfizer/BioNTech | mRNA-based vaccine |
| Moderna | mRNA-based vaccine |
| Sinovac | Inactivated |
| Sinopharm x 2 | Inactivated |
| Bharat | Inactivated |
| Chumakov | Inactivated |
| AstraZeneca/Oxford | Viral vector |
| Gamaleya | Viral vector |
| CanSino | Viral vector |
| Janssen | Viral vector |
| Federal Budgetary Research Institution State Research Centre, Russia | Peptide |
As at 1 March 2021, the count of potential vaccines in clinical trials is:
| Stage | Phase 1 | Phase 1/2 | Phase 2 | Phase 2/3 | Phase 3 |
| Vaccine Candidates | 25 | 24 | 6 | 5 | 12 |
There are an additional 14 trials that have been initiated in phases 1, 1/2 and 2 since our last report. There are 4 fewer at phase 3.
Vaccination programmes
Globally, the number of COVID-19 vaccine doses administered, and rates per population, are (link):
As at 4 March, a remarkable 284 million doses have been administered worldwide. Israel has the highest proportion of the population vaccinated.
The chart below illustrates the share of each population that have had at least one dose of a COVID vaccine.
In the UK, as of 4 March, 21.0m people have received a first dose of a COVID-19 vaccine, and 1.0m have received a second dose (link).
Priority groups for the initial phase of vaccinations were determined by Government following advice from the Joint Committee on Vaccination and Immunisation (JCVI) and included care home residents and their carers, people aged 70 years old and over, and frontline health and social care workers. It also includes people who are identified as being clinically extremely vulnerable to COVID-19.
The target of reaching 15m doses given by the 15th of February in the UK was achieved with all of those in priority groups 1-4 being offered a first dose of a COVID-19 vaccine. The vaccination programme has now moved into a second phase to include those in priority groups 5-9 (table below, link):
Challenges for the programme are now likely to include supply chain issues, and how to manage the second dose schedule concurrently with the ongoing first dose programme.
Real-world effectiveness of the Pfizer/BioNTech BNT162b2 vaccine and AstraZeneca ChAdOx1 vaccine against confirmed COVID-19, hospitalisations and deaths
In this pre-print (link), researchers from UK Public Health departments sought to estimate the effect of the Pfizer and AstraZeneca (‘AZ’) vaccines on confirmed symptomatic disease in those aged over 70 years in England.
Using a ‘test negative case control design’ (a type of study considered powerful in estimating vaccine effectiveness, where subjects testing positive are cases, and the negatives provide the control group), the odds ratios for testing positive for SARSCoV-2 in all vaccinated compared to unvaccinated individuals were estimated.
The aims of the analyses were to:
- Estimate the effect of vaccination on confirmed COVID-19 in adults aged >=70 years with one and two doses;
- Estimate vaccine effectiveness against the new variant of concern, VOC 202012/01;
- Estimate case hospitalisation and case fatality rates among vaccinated and unvaccinated cases.
Only individuals swabbed within 0-10 days of symptom onset were included in the analysis because sensitivity of PCR testing (true positive rate) decreases beyond 10 days after symptom onset.
The number of cases admitted to hospital within 14 days of the positive test, and the number of deaths within 21 days of the positive test, were estimated by vaccination status at the date of test (unvaccinated, vaccinated within 0-13 days, vaccinated at least 14 days before).
There were 156,930 pillar 2 PCR tested samples in individuals reporting symptoms within 10 days of the sample date which were linked to vaccination data in the National Immunisation Management System (NIMS). 44,590 (28%) were positive tests, 112,340 (72%) were negative.
Vaccine coverage by vaccine brand at February 21st 2021 (by positive and negative test) was:
Table 1: vaccine coverage by vaccine among cases and negative controls by age group
| Positive tests | |||||||
| AstraZeneca | Pfizer/BioNTech | Any vaccine | Unvaccinated | Total | |||
| Age | n | % | n | % | % | n | n |
| 70-74 | 10,073 | 50 | 4932 | 24 | 74 | 5214 | 20,219 |
| 75-79 | 5227 | 47 | 3196 | 28 | 75 | 2816 | 11,239 |
| 80-84 | 2320 | 36 | 2706 | 42 | 77 | 1487 | 6513 |
| 85-89 | 1355 | 35 | 1356 | 35 | 70 | 1180 | 3891 |
| ≥90 | 985 | 36 | 682 | 25 | 61 | 1061 | 2728 |
| Total | 19,960 | 45 | 12872 | 29 | 74 | 11,758 | 44,590 |
| Negative tests | |||||||
| AstraZeneca | Pfizer/BioNTech | Any vaccine | Unvaccinated | Total | |||
| Age | N | % | N | % | % | n | |
| 70-74 | 33,756 | 59 | 20,251 | 35 | 95 | 3137 | 57,144 |
| 75-79 | 14,605 | 50 | 13,375 | 45 | 95 | 1439 | 29,419 |
| 80-84 | 3955 | 28 | 9366 | 67 | 95 | 721 | 14,042 |
| 85-89 | 2243 | 30 | 4559 | 62 | 92 | 555 | 7357 |
| ≥90 | 1866 | 43 | 2061 | 47 | 90 | 451 | 4378 |
| Total | 56,425 | 50 | 49,612 | 44 | 94 | 6303 | 112,340 |
Early (pre 4 January vaccination) results for 80+ year olds
Results of odds of testing positive after vaccination with BNT162b2 for vaccinations administered prior to the 4th of January are shown in figure 2.
The odds of testing positive increased during the early period up to 7-9 days reaching 1.5 (95% CI, 1.23-1.77), and then began to decrease from 10-13 days post vaccination reaching 0.4 (95% CI, 0.32-0.54) during days 28-34 after which a similar level remained.
Compared with an unvaccinated baseline, this is equivalent to a vaccine effectiveness of 59%.
Figure 2: Adjusted odds ratios for confirmed case by interval after vaccination for BNT162b2, vaccinations administered prior to 4th January 2021, age >=80 years
Relative to the higher baseline risk observed during days 4-9 (vaccinated individuals had a higher odds of testing positive at this time, suggesting that vaccination was being targeted at those at higher risk of disease), the odds ratio was reported as 0.3 (95% CI, 0.22-0.41), equivalent to a vaccine effectiveness of 70%.
From 7 days after a second dose of BNT162b2 the odds ratio was 0.2 (95% CI, 0.14-0.32) and then 0.15 (95% CI 0.11-0.21) from 14 days after the second dose, indicating vaccine effectiveness of 85%.
Relative to the higher baseline risk seen during days 4-9, the odds ratio reaches 0.1 (95% CI, 0.07-0.15) equivalent to a vaccine effectiveness of 89%.
Results (post 4 January vaccination) for age >=70 years
Table 3: Adjusted odds ratios for confirmed case by interval after vaccination for both vaccines, vaccinations administered since 4th January 2021, age >=70 years
d1= interval after dose 1, d2= interval after dose 2. OR: odds ratios period adjusted by week of onset. aOR: odds ratios adjusted for age, period, sex, region, ethnicity, care home, imd quintile
The researchers report that results are similar for those identified to have VOC 202012/01 (Kent Covid variant).
Results of Hospitalisation for 80+ year olds
Hazard ratios for hospitalisation for both vaccines show significant reductions in risk.
Table 4: Risk of admission to hospital within 14 days of testing positive in vaccinated and unvaccinated cases aged over 80 years
| BNT162b2 | ChAdOx1 | |||||||
| Status | Hospitalisation | Hospitalisation | ||||||
| Total cases | n | % | Hazard ratio | Total cases | n | % | Hazard ratio | |
| Unvaccinated | 8892 | 1365 | 15.35 | 1.00 | 8892 | 1365 | 15.35 | 1.00 |
| Test date less
than 14 days after first dose |
2084 | 293 | 14.06 | 0.98
(0.86-1.11) |
562 | 64 | 11.39 | 0.98
(0.78-1.24) |
| Test date 14 days or more after first dose | 1400 | 128 | 9.14 | 0.57
(0.48-0.67) |
126 | 9 | 7.14 | 0.63
(0.41-0.97) |
| Total | 12,376 | 1786 | 14.43 | 9580 | 1438 | 15.01 | ||
The risk of hospital deaths within 21 days of a positive test by vaccination status among those aged >=80 years for BNT162b2 is shown in Table 5:
Table 5: Risk of death within 21 days of testing positive in vaccinated and unvaccinated cases aged over 80 years, BNT162b2
The hazard ratios for death compared to unvaccinated was 0.51 (CI 0.38-0.63) for those vaccinated at least 14 days prior to the test date. This indicates that vaccinated individuals who do become symptomatic cases have an additional 51% protection against death within 21 days of a positive test .
The researchers report that overall, this study provides early evidence that the vaccine is having a significant effect on COVID-19 cases in England.
Treatment
Throughout the pandemic the RECOVERY trial has been evaluating a range of potential treatments in the UK for COVID-19, and has recruited 177 hospitals and 33,000 patients. In the last month, the trial has expanded internationally, with Nepal and Indonesia the first countries to join. The number of treatments that are being investigated in the UK has expanded to the following:
- Colchicine (commonly used anti-inflammatory);
- Regeneron’s antibody cocktail (a combination of monoclonal antibodies directed against coronavirus);
- Aspirin (commonly used to thin the blood);
- Baricitinib (an immunomodulatory drug used in rheumatoid arthritis);
- Dimethyl fumarate (an immunomodulator drug used in psoriasis and multiple sclerosis).
The inclusion of baricitinib from February 2 represents the 10th potential treatment to be tested through the RECOVERY trial. It is thought that baricitinib may prevent the hyper-inflammatory state seen in patients with severe COVID-19 through interrupting cytokine molecule signalling. The Adaptive Covid-19 Treatment Trial across 67 sites in 8 countries has already investigated the use of baricitinib in combination with remdesivir. The trial found improvements in recovery time and clinical status, but the numbers involved were too small to generate significant findings and did not consider the use of baricitinib in combination with steroids.
Testing
The 9th round of testing from the REACT-1 study reported yesterday indicated that the prevalence of SARS-CoV 2 infections has fallen by 2/3rds since the 8th round in January to 49 infections per 10,000 people. These results were based on swabs from a population of 165,400 volunteers in England between 4-23 February.
More detailed investigation of trends over this period indicated there were small increases in the rate of infection in London, South East, East Midlands and West Midlands. The rates of infection in different ethnic groups in this round showed infection rates of 2.1%, 0.83% and 0.45% in the Pakistani, Black and white populations respectively. Comparisons with the previous round indicate that the rate of reduction is comparable between the Black and white populations, but have only reduced by approximately 20% in the Pakistani population.
Table 6 illustrates the prevalence of positive swabs from each of the nine rounds of testing so far in the REACT-1 study.
Table 6. Unweighted and weighted prevalence of swab-positivity across nine rounds of REACT-1
Antibodies
The fifth round of the REACT-2 study investigated IgG antibody prevalence across a population of 172,000 between 26 January-8 February. This was the first round for which results were separately provided for vaccinated and unvaccinated individuals.
The survey found that high levels of IgG antibodies were seen after 21 days in all age groups for those that had received two doses of the Pfizer/BioNTech vaccine or a single dose in those that had a prior suspected COVID-19 infection. However, Table 7 from the pre-print study on MedRxIV indicates that antibody prevalence rates are less than 50% for those over age 70 after a single dose.
Table 7. IgG positivity 21 days or more after one and two Pfizer/BioNTech doses, by age group
These results do not necessarily contradict the earlier study from NHS Scotland that found an 85% reduction in hospitalisation rates 28 days after a single vaccine dose. Antibodies do not provide a complete picture of the strength of the immune response. However, these results may imply that a single Pfizer/BioNTech dose is less likely to prevent mild to moderate symptoms and onward transmission in elderly persons, and are consistent with analysis of the likelihood of symptomatic infection from Public Health England.
This study questions current proposals to provide the 2nd dose 12 weeks after the 1st dose for all priority groups. It may represent a more effective use of vaccine capacity to reduce the separation between doses for the most elderly age groups, and delay the first vaccination of younger age priority groups by a number of weeks.
Long COVID
The ONS have updates the long COVID prevalence estimates for the UK using the UK Coronavirus Infection Survey (CIS). (link) Data from 9063 respondents to this survey who tested positive were used for this analysis.
The CIS is a survey sample of respondents randomly selected from the UK population (excluding communal establishments) who are followed-up weekly for the first month from enrolment, followed by monthly for a up to a year. At each visit, respondents are swab tested for COVID-19 and describe their current symptoms (from a list of 12 common COVID-19 symptoms) to the interviewer.
Figure 1. Kaplan-Meier estimate of the percentage of UK CIS respondents still reporting at least one symptom over time following COVID-19 infection
The graph displays the estimate of the percentage of respondents still reporting at least one symptom following COVID-19.
22% (95% CI: 21.2% to 23.2%) of respondents were still reporting at least one symptom at 5 weeks following COVID-19 infection, while 10% (7.4% to 13.1%) had symptoms at 12 weeks.
The most common symptoms at 5 weeks were reported to be:
- fatigue (13%)
- cough (12%)
- headache (11%)
- loss of taste and/or smell (10%)
- myalgia (9%)
Figure 2. Percentage of UK CIS respondents still reporting at least one symptom 5 weeks after COVID-19 infection, stratified by sex and age group
This graph displays long COVID prevalence by sex and age. The highest prevalence is seen in those aged 35-49 years.
Worryingly, persistent symptoms are being reported in children.
The ONS estimates that during the week commencing 27 December 2020, 301,000 people in private households in England were living with symptoms that had persisted for between 5 and 12 weeks.
5 March 2021
