Tuesday, 8 June 2021

Coronavirus (43) Mass asymptomatic testing of SARS-CoV-2 using lateral flow devices (cont’d)

Coronavirus (43) Mass asymptomatic testing of SARS-CoV-2 using lateral flow devices (cont’d)
Continued from my last blog post.
Limitation of lateral flow tests
The lateral flow test kit from Innova for detection of SARS-CoV-2 infections has been tested by Public Health England and validated by the UK government.1,2 It was initially tested among 132 candidates when the UK government were considering the use of lateral flow devices (LFDs) in mass-testing for COVID-19 in an asymptomatic population.1

The test report showed that all the tested lateral flow devices have a viral antigen detection rate of >90% at 100,000 RNA copies/ml (for comparison, only 3,600 to 10,000 copies/ml of virus in the sample is already enough to be detected by RT-PCR, which is more than ten times as sensitive). The study found a kit failure rate of 5.6% from 8951 Innova SARS-CoV-2 Antigen Rapid Qualitative Tests. The most common reason for kit failure was poor transfer of the liquid within the device from the reservoir onto the test strip. 1

The false positive rate was 0.32% from 6954 Innova tests. This means that for every 1,000 people tested, only 3 people would get a false positive result. The study also found that the sensitivity (the detection rate of positive cases) across the sampling cohort is significantly dependent on the test operator. Sensitivity of the tests performed by laboratory scientists was 78.8%, trained healthcare-workers was 70%, while the self-trained members of the public was 57.7%.1

The above study showed that the kit failure rate for the tests is not low, and they tend to give a more accurate result only if a sample with higher viral concentration is being tested and the user performing the test is well-trained. This means the overall accuracy of the lateral flow tests is generally lower among asymptomatic people who are not well-trained and who have a generally lower viral concentration.

When it comes to the real world evaluation of Innova SARS-CoV-2 Antigen Rapid Qualitative Test, the sensitivity of the test is found to be much lower than the above report. The Innova lateral flow test was used in a mass test of the population in Liverpool last November.3 By evaluation of the performance of the Innova lateral flow test against RT-PCR testing using data from 5,869 people, it was found that 60% of infected people could not be detected by the lateral flow tests. On the other hand, the test performed better for detecting cases in people with higher viral loads, with test sensitivity in this group at 66.7%.3 Similar to the result from the other study, the specificity was 99.9% in this study.1,3 This means the positive results from the lateral flow tests are highly accurate.

Based on these research studies, the general sensitivity of the lateral flow tests are 40–76%, which means that about half of infected people may be missed.1,3,4 Those carrying COVID-19 who were wrongly told they were free of the virus could transmit to more people than those who do not have the tests, due to a false sense of security. Therefore, many scientists called on the government at least to pause the rollout of rapid asymptomatic testing using the Innova tests, as they are sceptical that the lateral flow tests are able to control effectively the transmission of infection.5,6

Can the lateral flow test detect COVID-19 variants?
There has no research paper or data available yet on the efficiency of the Innova SARS-CoV-2 Antigen Rapid Qualitative Test to detect the Kent and Indian variants which are now prevalent in the UK. The planned rollouts of lateral flow tests in schools were paused because of concerns about the risk of missing cases caused by the new and more transmissible SARS-CoV-2 variants.7

Where can we get the free lateral flow test?
After reading all the information about the free of charge lateral flow test scheme, you might want to try to have one yourself. The free rapid lateral flow tests are being made available by the government in England. As long as you are in England, aged 11 or above, and have no COVID-19 symptoms, you can order one pack of lateral flow tests per day online and it will be delivered to your home. Each pack contains 7 tests.6

​ The tests can also be collected at local PCR test sites and most of the local pharmacies in England. It is very important to remember that the tests are just for asymptomatic people: if you have COVID-19 symptoms, you should not go outside to collect a test; instead, you should order a PCR test and self-isolate.6

Who could benefit from the free lateral flow tests?
The sensitivity of lateral flow tests are in doubt, and the usefulness of the lateral flow tests being used as a tool to control the transmission of infection is being questioned by some scientists. However, as long as the tests are repeated twice a week as suggested by the government, there is still a chance of the asymptomatic infections being detected. Therefore, the free lateral flow test scheme available in England provides certain degree of protection for the households who have members working in patient-facing or customer-facing sectors.

However, you have to remember that the test on average misses about half of the COVID-19 infectious cases, i.e. a negative result does not rule out a COVID-19 infection. If your result is negative from the lateral flow test, it is very important to still follow all the current restrictions imposed by the government.

1. Peto T & UK COVID-19 Lateral Flow Oversight Team. COVID-19: rapid antigen detection for SARS-CoV-2 by lateral flow assay: a national systematic evaluation for mass-testing. medRxiv. 2021; (published online Jan 26.) (preprint). https://doi.org/10.1101/2021.01.13.21249563
(Later published online in Lancet, May 29, 2021. DOI:https://doi.org/10.1016/j.eclinm.2021.100924)
2. Order coronavirus (COVID-19) rapid lateral flow tests. GOV.UK website. https://www.gov.uk/order-coronavirus-rapid-lateral-flow-tests
3. Liverpool COVID-19 community testing pilot. Interim evaluation report by the University of Liverpool. 23 December, 2020. https://www.liverpool.ac.uk/media/livacuk/coronavirus/Liverpool,Community,Testing,Pilot,Interim,Evaluation.pdf
4. RT-LAMP assay: Fail to detect positive cases more than 50% in November in Manchester. “Covid-19: Rapid test missed over 50% of positive cases in Manchester pilot. BMJ 2020; 371 doi: https://doi.org/10.1136/bmj.m4323 (Published 06 November 2020) Cite this as: BMJ 2020;371:m4323”
5.UK government must urgently rethink lateral flow test roll out, warn experts. The BMJ news, 11/01/21. https://www.bmj.com/company/newsroom/uk-government-must-urgently-rethink-lateral-flow-test-roll-out-warn-experts/
6. Covid-19: UK regulator approves lateral flow test for home use despite accuracy concerns. BMJ news, 2020; 371 doi: https://doi.org/10.1136/bmj.m4950 (Published 23 December 2020)
7. Mass testing of COVID-19: January update on lateral flow tests. UK Parliament Post, 29 January 2021. https://post.parliament.uk/mass-testing-for-covid-19-january-update-on-lateral-flow-tests/

Saturday, 22 May 2021

Coronavirus (42) Mass asymptomatic testing of SARS-CoV-2 using lateral flow devices

Coronavirus (42) Mass asymptomatic testing of SARS-CoV-2 using lateral flow devices
In order to contain the spread of COVID-19, in addition to the national lockdown and nationwide COVID-19 vaccination, the UK government also use reverse-transcription polymerase chain reaction (RT-PCR) testing of nose/throat swabs, contact tracing procedures, and mobile applications to identify close contacts of infected symptomatic individuals.

In addition to the above measures, the government also rolled out mass asymptomatic testing on 9th April, aiming to identify people with COVID-19 who are not displaying any symptoms. This testing programme allows everyone in England to access two COVID-19 tests a week, free of charge, even if they do not have any symptoms.1 Ideally, by quickly identifying the asymptomatic patients and having these people self-isolate, and through the rapid finding and testing of their close contacts, the spread through the community could be interrupted.1

The programme uses the lateral flow test kit, SARS-CoV-2 Rapid Antigen Lateral Flow Qualitative Test, from Innova. Since many may have heard of the programme but not used the test kit, this and the coming blog posts provide more information about the test so that you can have a better idea of it.

What are lateral flow tests?
Lateral flow tests are basically assays designed to test for different protein targets. A sample is placed on a conjugation pad where the analyte (or antigen) of interest is bound by conjugated antibodies. The analyte-antibody mix then migrates along a membrane by capillary flow, across both ‘test’ and ‘control’ strips. These strips are coated with antibodies detecting the analyte of interest, and a positive test is confirmed by the appearance of coloured control and test lines.2

As no laboratory processing is needed, lateral flow tests can be performed in the area convenient to the person being tested. Moreover, a short turnaround time, relatively higher test accuracy and the economic affordability make the tests suitable for mass testing. In fact, the tests have been used for rapid testing in communities and workplaces.3

Innova SARS-CoV-2 Antigen Rapid Qualitative Test is a disposable test kit, like a home pregnancy test kit. It detects nucleocapsid protein antigen from SARS-CoV-2 in direct nose and/or throat swabs. A positive result is seen as a dark band or a fluorescent glow on the “test” strip after about 30 minutes.4 The appearance of two lines on both the “test” and “control” strips indicates that the test is positive. The appearance of one line on the “control” strip only indicates a negative result. However, if the “control” strip line does not appear after 30 minutes of waiting, this means the test has failed to work and should be retaken.

The whole procedure to perform the test by yourself is written clearly in the instruction booklet included in each pack of the test kit. It is interesting to find that, according to the instruction booklet distributed to NHS staff, NHS recommends only a nasal swab is used and the sample is taken in a different way to that described in the packaged instructions for use, with more rotation of the swab at a lower level of penetration, to enable easier self-administration of the test.5

Storage precautions
Test kits should be stored at room temperature. It is very important to keep the test kits in an area with no direct sunlight, neither should the test kit be kept in a fridge or freezer. High or low temperatures can denature or inactivate the antibodies in the kit and affect the result.

Instructions after knowing the results
If you are taking the lateral flow test at home, you should register the results, whether positive or negative, online or by calling 119. If you get a positive test result, everyone in your household must self-isolate according to the government guidelines.6 Moreover, you need to take an RT-PCR test to further confirm the result.1,6

If the test result is invalid, you need to retake the test with a new test kit.

1. Mass asymptomatic COVID-19 testing: Strategy and accuracy. Research briefing, House of Commons Library, 12 May, 2021. https://commonslibrary.parliament.uk/research-briefings/cbp-9223/
2. O'Farrell B. Evolution in lateral flow-based immunoassay systems. Lateral Flow Immunoass. 2009; p 1-33. https://doi.org/10.1007/978-1-59745-240-3_1.
3. Peto T & UK COVID-19 Lateral Flow Oversight Team. COVID-19: rapid antigen detection for SARS-CoV-2 by lateral flow assay: a national systematic evaluation for mass-testing. medRxiv. 2021; (published online Jan 26.) (preprint). https://doi.org/10.1101/2021.01.13.21249563
(Later published online in Lancet, May 29, 2021. DOI:https://doi.org/10.1016/j.eclinm.2021.100924)
4. Primary Care Supply webpage for Innova SARS-CoV-2 Antigen Rapid Qualitative Test. https://www.primarycaresupplies.co.uk/innova-sars-cov-2-antigen-lateral-flow-rapid-test-kit-box-of-20/
5. A guide for healthcare staff self-testing for coronavirus using a Lateral Flow Device (LFD). By NHS. https://www.england.nhs.uk/coronavirus/wp-content/uploads/sites/52/2020/11/LFD_NHSStaff_A4_161120_.pdf
6. Order coronavirus (COVID-19) rapid lateral flow tests. GOV.UK website. https://www.gov.uk/order-coronavirus-rapid-lateral-flow-tests

Saturday, 15 May 2021

Coronavirus (41) Nationwide COVID-19 immunization in Israel

Coronavirus (41) Nationwide COVID-19 immunization in Israel
The nationwide vaccination programmes for COVID-19 have been rolled out in several countries. Surveillance report from the Israel vaccination programme which uses BNT162b2 (by Pfizer and BioNTech, mRNA vaccine) has been published early this month.1 In contrast with the report from the UK which provides data on the effectiveness of the BNT162b2 Pfizer vaccine after the first dose, the surveillance report from Israel provides data on the effectiveness of BNT162b2 after the second dose. When taken together with the data from the report from the UK, the data from Israel should provide us a more comprehensive idea of the efficacy of BNT162b2 in the general population. Let us have a look at this report.

Background of the surveillance report from Israel
The report from Israel was done by the Israel Ministry of Health and by Pfizer. Israel launched the vaccination campaign on 20 December 2020, 12 days after the UK. Moreover, Israel used only BNT162b2 (Pfizer) for its nationwide vaccination programme.

The study analyzed nationwide surveillance data from 24 January to 3 April, 2021. The start of the study period corresponded to 14 days after the first individuals received their second BNT162b2 dose. By 3 April 2021, 72.1% of people aged 16 years and older were fully vaccinated with two doses of BNT162b2. Individuals with a history of severe allergic reactions to the vaccine components were not eligible to receive the vaccine.

The study aimed to estimate the effectiveness of two doses of BNT162b2 (second dose injected 21 days after the first dose, in accordance with the suggestion from Pfizer) against a range of SARS-CoV-2 outcomes (asymptomatic infection, symptomatic infection, and COVID-19-related hospitalisation, severe or critical hospitalisation, and death) in the general population in Israel. The study also evaluated the nationwide public-health impact following the widespread introduction of the vaccine.

The vaccine’s effectiveness against SARS-CoV-2 outcomes was calculated on the basis of incidence rates in fully vaccinated individuals (who had received the second dose of vaccine and had passed 7 days) compared with rates in unvaccinated individuals (who had not received any doses of the vaccine).

The data from the observational surveillance report from Israel vaccination campaign The report showed that BNT162b2 is highly effective across all age groups (16–24, 25–34, 35–44, 45–54, 55–64, 65–74, 75–84, and ≥85 years) in preventing a range of SARS-CoV-2 outcomes. Among adults aged 16 years and older, the vaccine effectiveness was 95.3% against SARS-CoV-2 infection at 7 days or longer after the second dose: 91.5% against asymptomatic SARS-CoV-2 infection, 97.0% against symptomatic COVID-19, 97.2% against COVID-19-related hospitalisation, 97.5% against severe or critical COVID-19-related hospitalisation, and 96.7% against COVID-19-related death.

According to the test samples of people with COVID-19 taken during the period of the study, 94.5% of the SARS-CoV-2 infections were from the B.1.1.7 variant. The test results indicated that BNT162b2 is highly effective against the SARS-CoV-2 variant B.1.1.7, which was first identified in the UK, and later reported in Israel on 23 December, 2020.

In all age groups, as vaccine coverage increased, the incidence of SARS-CoV-2 infection declined. The early reductions in incident cases of SARS-CoV-2 infections were observed in older age groups, which had higher and earlier vaccine coverage. The declines were observed for people aged 65 years and older starting in mid-January 2021, while the reductions were observed 3 to 4 weeks later among people aged between 16 and 24, when vaccine coverage for this age group began to increase. The incidence of COVID-19 hospitalisations, severe or critical hospitalisations, and deaths, were also declined accordingly.

The figures from the report showed that the declines of SARS-CoV-2 incidence continued even after the two phases of reopenings on 7 February and 21 February 2021, and the final lifting of the lockdown on 7 March 2021. These findings suggest that the vaccine coverage was the main contributor for the reductions in the incidence of SARS-CoV-2 infections, while the next is the nationwide lockdown measure.

Moreover, the SARS-CoV-2 incidence remained low even after the two phases of reopenings. This further suggests that vaccine coverage might provide a sustainable path towards resuming normal activity nationally.

The UK government has started giving BNT162b2 (Pfizer) to most adults aged under 40.2 The report from Israel demonstrates that two doses of BNT162b2 are highly effective in preventing different SARS-CoV-2 infection outcomes, including severe disease and death, among different age groups. Moreover, there were steep and sustained declines in SARS-CoV-2 infection rate corresponding to increasing vaccine coverage. Therefore, unless you have a history of severe allergic reactions and are defined as not suitable to get the BNT162b2 Pfizer vaccination,3 it is worth receiving a full dosage of the vaccine in order to get protection from COVID-19.

1. E.J. Haas, F.J. Angulo, J.M. McLaughlin, et al. Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel: an observational study using national surveillance data. Lancet, May 5, 2021 https://doi.org/10.1016/S0140-6736(21)00947-8 . Online ahead of print.
2. Under 40s to be offered alternative to AZ vaccine. By James Gallagher. BBC news, 7th May, 2021. https://www.bbc.co.uk/news/health-57021738
3. Pfizer-BioNTech COVID-19 vaccine overview and safety. Centers for Disease Control and Prevention. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/different-vaccines/Pfizer-BioNTech.html

Friday, 7 May 2021

Coronavirus (40) Nationwide COVID-19 immunization in the UK

Coronavirus (40) Nationwide COVID-19 immunization in the UK
Five months have passed since the UK started its vaccination rollout last December. You might wonder the concerns about the side-effects after vaccination and the efficacy of the vaccines against COVID-19 in the general population. Surveillance reports from the UK’s vaccination programme using Pfizer-BioNTech (BNT162b2, mRNA vaccine) and Oxford-AstraZeneca (ChAdOx1 nCoV-19, non-replicated adenovirus vectored vaccine) COVID-19 vaccines has been published recently.1 Although the vaccination campaign in the UK is still ongoing, the data from the report gives us some idea of the above issues.

Background of the surveillance report from the UK
The surveillance report from the UK analysed data collected from individuals using a COVID Symptom Study app, which was developed by a health science company ZOE and was launched at the end of March 2020. The research is led by ZOE co-founder, Professor Tim Spector at King’s College London. Data collected is shared with and analysed by King's College London and ZOE research teams.

The reports covered the period from the first day of the vaccine campaign, 8 December 2020, to 10 March 2021. The nationwide vaccination programme in the UK prioritized senior citizens and the most vulnerable groups.2 According to the COVID-19 vaccine monitoring statistics data provided by the NHS,3 by 14th March, at least one dose of vaccine had been given to the adults aged over 50, front-line health and social care workers (those who participated in the ZOE study had a median age of 46.1 years),4 staff working in care homes, clinically extremely vulnerable individuals, and the adults aged 16 to 65 years in an at-risk group.

The BNT162b2 (Pfizer) vaccination was first rolled out on 8 December 2020, while the ChAdOx1 nCoV-19 (Oxford/AstraZeneca) vaccination was first rolled out on 4 January 2021. Both vaccines are two-dose regimens. However, individuals will be given the second dose at 10-12 weeks after the first dose, rather than 21 days as per the guidance of the vaccine manufacturers. By the end of the analysis period, some people already had both doses of BNT162b2 (Pfizer) vaccines.

The COVID Symptom Study app allows self-reporting of systemic and local side effects for individuals who received one or both doses of the BNT162b2 (Pfizer) vaccine, or the first dose of the ChAdOx1 nCoV-19 (Oxford/AstraZeneca) vaccine. Side effects were monitored for the following 8 days after a vaccination. A subset of individuals also reported receiving a test for SARS-CoV-2 infection by either PCR or lateral flow test. The study also compared infection rates in a subset of vaccinated individuals (subsequently tested for SARS-CoV-2 with PCR or lateral flow tests) with infection rates in unvaccinated controls.1

The side effects of both vaccines
During the analysis period, the COVID Symptom Study app received 627,383 reports of individuals being vaccinated: 282,103 received at least one dose of BNT162b2 (Pfizer), while 345,280 individuals reported being vaccinated with one dose of ChAdOx1 nCoV-19 (Oxford/AstraZeneca).

From the self-report system, it seems that systemic (whole body) side-effects were higher in participants who received ChAdOx1 nCoV-19 (Oxford/AstraZeneca). Systemic side-effects were reported by 13.5% and 22.0% of individuals after the first dose and the second dose respectively of BNT162b2 (Pfizer), while 33.7% of individuals receiveing the first dose of ChAdOx1 nCoV-19 (Oxford/AstraZeneca) reported systemic side-effects. The most commonly reported systemic side-effects were fatigue and headache for both vaccines. They were most frequently reported within the first 24 hours after vaccination, and lasted for about 1 day.

The reported local side-effects were more frequent than the systemic side-effects. However, by contrast with the systemic side-effects, local side-effects were more frequent in participants who received BNT162b2 (Pfizer): 71.9% and 68.5% of individuals reported local side-effects after the first dose and the second dose of BNT162b2, respectively, while 58.7% of individuals reported local side-effects after the first dose of ChAdOx1 nCoV-19. The most frequent local side-effects are tenderness and local pain around the injection site, which occurred most often on the day after injection and lasted for about 1 day. The less frequent side-effects include allergic skin reactions such as skin burning, rashes, and red welts on the lips and face, which was reported in 1.7% of 627,383 users across both types of vaccine.

Both systemic side effects and local side effects of both vaccines were more common among individuals with previous SARS-CoV-2 infection than among those without known past infection. After the first dose of BNT162b2 (Pfizer), systemic side effects and local side effects were 2.9 times and 1.2 times as high among individuals with previous SARS-CoV-2 infection than among those without known past infection. Meanwhile, after ChAdOx1 nCoV-19 (Oxford/AstraZeneca) vaccination, systemic side-effects and local side-effects were 1.6 times and 1.4 times as high among individuals with previous SARS-CoV-2 infection than among those without known past infection. Similar findings had been reported before.5,6 It seems that the previous infection leads to a higher immune response, which is reflected by the systemic side-effects, in a subsequent infection.

In line with the above findings, among the individuals (28,207) who reported having two BNT162b2 (Pfizer) doses, a higher percentage of systemic side-effects were being reported in individuals after the second dose. There were 3325 (11.7%) reporting at least one systemic side effect after the first dose, compared with 6216 (22.0%) after the second dose.

Infection rates after the vaccination of both vaccines
The study analysed infection rates at 0–4, 5–11, 12–20, 21–44, and 45–59 days after vaccination. It was found that the infection risk was significantly reduced starting at 12 days after the first dose of BNT162b2 (Pfizer), reaching 69% at 21–44 days and 72% after 45–59 days. For ChAdOx1 nCoV-19 (Oxford/AstraZeneca), the risk of infection was significantly reduced starting at 12 days after the first dose, reaching 60% later on.

Moreover, the data showed that the vaccines were more effective in younger and slimmer people with no more than one illness. For both vaccines, the reduction of infection was more significant in individuals aged 55 years or younger than in individuals older than 55 years; it was also more significant in those without comorbidity than in those with one or more comorbidities, and in individuals with a BMI of less than 30 kg/m2 than in those with BMI of 30 kg/m2 or higher.

The surveillance report showed us that the systemic side-effects of both vaccines, BNT162b2 and ChAdOx1 nCoV-19, are not highly prevalent. And the findings that the efficacy of the two vaccines are more than 60% 12 days after the injection should give us confidence to have vaccination if we have not had one. This should also encourage the individuals to have the second dose in order to get a higher protection from the vaccine.

1. C. Menni, K. Klaser, A. May, et al. Vaccine side-effects and SARS-CoV-2 infection after vaccination in users of the COVID Symptom Study app in the UK: a prospective observational study. Lancet Infect Dis., 2021 Apr 27. S1473-3099(21)00224-3. doi: 10.1016/S1473-3099(21)00224-3.
2. COVID-19 vaccination first phase priority groups. NHS website. Updated 23 April 2021. https://www.gov.uk/government/publications/covid-19-vaccination-care-home-and-healthcare-settings-posters/covid-19-vaccination-first-phase-priority-groups
3. COVID-19 vaccination statistics. By NHS. https://www.england.nhs.uk/statistics/wp-content/uploads/sites/2/2021/03/COVID-19-weekly-announced-vaccinations-18-March-2021.pdf
4. V.J. Hall, S. Foulkes, A. Saei, et al. COVID-19 vaccine coverage in health-care workers in England and effectiveness of BNT162b2 mRNA vaccine against infection (SIREN): a prospective, multicentre, cohort study. Lancet. 2021; (published online April 23.)
5. F. Krammer, K. Srivastava, and V. Simon. Robust spike antibody responses and increased reactogenicity in seropositive individuals after a single dose of SARS-CoV-2 mRNA vaccine. medRxiv, 2021; published online Feb 1. doi: https://doi.org/10.1101/2021.01.29.21250653
6. J. Wise. COVID-19: people who have had infection might only need one dose of mRNA vaccine. BMJ, 2021 Feb 2;372:n308. doi: 10.1136/bmj.n308.