Coronavirus (45) Nutrients help to combat COVID-19 (cont'd)

Coronavirus (45) Nutrients help to combat COVID-19 (cont’d)
In addition to the vitamins mentioned in my last blog post, minerals such as iron, zinc, selenium and copper are also essential for good immunity. They are required in smaller quantities and are therefore called trace minerals. Let us have a look at the same two review articles^1,2 used in the last blog post, on how different trace minerals can protect ourselves from infectious diseases.

Copper
Copper itself is an antimicrobe. Copper supports neutrophil, monocyte and macrophage function and natural killer cell activity.

People on a low copper diet have decreased lymphocyte proliferation and decreased production of IL-2, which is important for immune response. Children with Menke’s syndrome, a rare congenital disease with no circulating copper-carrying protein caeruloplasmin, show immune impairments and have increased bacterial infections and pneumonia. Analysis of studies on Chinese children showed that those with recurrent respiratory tract infection were more likely to have low levels of copper in their hair.¹

Iron
Iron is a trace mineral that we should be careful about the amount we take in. Iron is required for both host and pathogen. Iron deficiency can impair host immunity, while iron overload can cause oxidative stress to propagate harmful viral mutations.²

Iron deficiency has harmful effects on immune function, including impairment of: 1. the ability to generate reactive oxygen species for the killing of harmful microorganisms; 2. bacterial killing; 3. natural killer cell activity; 4. T lymphocyte proliferation, and 5. production of T helper 1 cytokines. These in turn increase susceptibility to infection.¹

On the other hand, infections caused by organisms that spend part of their life-cycle intracellularly may actually be enhanced by iron. In the children living in tropical regions, iron at doses above a particular threshold has been associated with increased risk of malaria and other infections, including pneumonia. Thus, iron intervention in malaria-endemic areas is not advised.¹ Moreover, a study giving iron (50 mg on each of 4 days a week) to iron-deficient schoolchildren in South Africa increased the risk of respiratory infections.¹

In general, the harmful consequences of iron overdoses on infections include: 1. Impairment of immune function; 2. Excess iron favours damaging inflammation; 3. Helping the growth of pathogens that require iron.

Selenium
Selenium deficiency adversely affects several components of both innate* and acquired immunity,** and increases susceptibility to infections.¹

It is of concern to find that dietary selenium deficiency induces rapid mutation of benign variants of RNA viruses to virulence. Deficiency in selenium can cause oxidative stress in the host, and can alter a viral genome so that a normally benign or mildly pathogenic virus can become highly virulent.² Selenium could assist a group of enzymes that, in concert with vitamin E, work to prevent the formation of free radicals and prevent oxidative damage to cells and tissues.

It was reported that combination of selenium with ginseng stem-leaf saponins could induce immune response to a live bivalent infectious bronchitis coronavirus vaccine in chickens.² Therefore, the review article written by Zhang et al suggests that selenium supplementation could be an effective choice for the treatment of novel variants of COVID-19.²

You may wonder how much selenium we need to maintain the normal function of our immunity. It was found that selenium supplementation with 100 to 300 µg/day could improve various aspects of immune function in humans including in the elderly. Selenium supplementation of 50 or 100 µg/day in adults in the UK with low selenium status improved some aspects of their immune response to a poliovirus vaccine.¹

Zinc
Zinc has an important role in maintaining and developing immune cells of both the innate* and adaptive immune system.***

Especially you may find it interesting that zinc seems to play an important role in antiviral defence. It was found to inhibit the RNA polymerase required by RNA viruses to replicate. Moreover, zinc supports proliferation of CD8+ cytotoxic T lymphocytes, key cells in antiviral defence. These findings suggest that zinc might play a key role in host defence against the RNA virus SARS-CoV-2 that cause COVID-19.¹ In fact, the combination of zinc and pyrithione at low concentrations inhibits the replication of SARS coronavirus.²

Zinc deficiency has a marked impact on bone marrow by decreasing the number of immune precursor cells. Therefore, zinc is important in maintaining T and B lymphocyte numbers. Moreover, antibody production is decreased in zinc deficiency. Zinc deficiency also impairs many aspects of innate immunity, including phagocytosis and natural killer cell activity. Patients with the zinc malabsorption syndrome, acrodermatitis enteropathica, display severe immune impairments and increased susceptibility to bacterial, viral and fungal infections.¹

Correcting zinc deficiency lowers the likelihood of respiratory and skin infections. Recent reviews and analysis of trials with zinc reported shorter durations of common cold in adults, reduced incidence and prevalence of pneumonia in children, and reduced mortality when given to adults with severe pneumonia.¹

Conclusion
After reading the two blog posts on the different nutrients and their importance in fighting against infection, we understand we should have a balanced diet in order to maintain our immune system to prevent respiratory diseases such as COVID-19. No single nutrient should be left out in order to attain the optimum condition of our immune system for health.

As new pathogens responsible for influenza continually emerge, and outbreaks of new variants of the SARS-CoV-2 virus are highly possible, it is especially necessary to have a dietary regimen that includes all the nutrients in order to reduce the adverse effects from new or mutating pathogens.



*The innate immune system is the body’s first line of defense against germs. The innate immune system consists of 1. skin and mucous membranes that forms a physical barrier against germs; 2. immune system cells (defense cells) and proteins that are activated upon inflammation; 3. white blood cells (leukocytes) that kill bacteria or viruses, by phagocytosis, that enter the body; 4. natural killer cells specialized in identifying cells that are infected by a virus, and then destroy the cell surface using cell toxins.³
Since the innate immune system responds in the same way to all germs and foreign substances, it is also referred to as the "nonspecific" immune system. It acts very quickly: it makes sure that bacteria that have entered the skin through a small wound are detected and destroyed on the spot within a few hours. However, the innate immune system has only limited power to stop germs from spreading.³
**“Acquired immunity is a type of immunity that develops when a person’s immune system responds to a foreign substance or microorganism, or that occurs after a person receives antibodies from another source. The two types of acquired immunity are adaptive and passive. Adaptive immunity occurs in response to being infected with or vaccinated against a microorganism. The body makes an immune response, which can prevent future infection with the microorganism. Passive immunity occurs when a person receives antibodies to a disease or toxin rather than making them through his or her own immune system.” (from online NCI (National Cancer Institute) dictionary. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/acquired-immunity)
***The adaptive immune system takes over if the innate immune system is not able to destroy the germs. The adaptive immune system is made up of 1. T lymphocytes in the tissue between the body's cells; 2. B lymphocytes which are also found in the tissue between the body's cells; 3. antibodies in the blood and other bodily fluids.
The adaptive immune system specifically targets the type of germ that is causing the infection. It first identifies the germ, which makes it slower to respond than the innate immune system, and then it destroys it. It can "remember" germs, so the next time a known germ is encountered, the adaptive immune system can respond faster.



References
1. P.C. Calder. Nutrition, immunity and COVID-19. Review. BMJ Nutrition, Prevention & Health. 2020 May 20;3(1):74-92.
2. L. Zhang, and Y. Liu. Potential interventions for novel coronavirus in China: A systematic review. Journal of Medical Virology, 2020 May 92(5):479-490.
3. The innate and adaptive immune systems. InformedHealth.org. Cologne, Germany: Institute for Quality and Efficiency in Health Care (IQWiG); 2006-. https://www.ncbi.nlm.nih.gov/books/NBK279396/

Coronavirus (44) Nutrients help to combat COVID-19

Coronavirus (44) Nutrients help to combat COVID-19
Since the outbreak of COVID-19 in the UK, which led to the first national lockdown in March 2020, the pandemic has already lasted for more than 15 months. During this period of time, many countries in the world experienced several waves of COVID-19 outbreaks, and quite a few major variants of the SARS-CoV-2 virus emerged. For the UK, the country has been attacked by the wild type, the variant from South Africa (Beta variant, B1.351), the variant from Kent (Alpha variant, B.1.1.7), and recently the variant that originated from India (Delta variant, B1.617.2).

The existing therapies and vaccines against COVID-19 were designed based on the SARS-CoV-2 virus first identified. The longer the virus spread among people, the higher the chances that the virus would mutate. The mutated variants that later become dominant are usually more virulent, and they are more resistant, to various degrees, to the existing therapies and vaccines. Unless we could produce a specific therapy or vaccine in time for an emerged variant, a good immune system, which is able to respond promptly and appropriately to different challenges, is very important to protect us against any SARS-CoV-2 variants.

Optimal nutritional status and lifestyle habits are essential to keeping our immune systems working properly. Here in this blog post, I would like to share with you findings from two review articles on how different nutrients can help us protect ourselves from infectious diseases.^1,2 This might give us an idea of what we could prepare for our meals in order to strengthen our health to combat coronavirus-related diseases.

Vitamin A
Vitamin A has been called an “anti-infective vitamin”. It is essential for body's defences against infection as it is important for normal differentiation of epithelial tissue.*^1,2 Lack of vitamin A is associated with increased susceptibility to respiratory infections, diarrhoea and severe measles.

Moreover, vitamin A is important for immune cell maturation and function: Vitamin A controls maturation of neutrophils, macrophages, natural killer cells, dendritic cells, and CD4+ T lymphocyte, which are involved in the killing of pathogens.¹

As we are undergoing a national vaccination program in the UK, it is also relevant to note that vitamin A deficiency can impair the body’s response to vaccination. Vitamin A’s metabolite, retinoic acid, is required for normal functioning of B lymphocytes, including antibody generation. An example from Indonesian children with vitamin A deficiency showed a higher antibody response to tetanus vaccination after providing them with vitamin A, suggesting that lack of vitamin A can impair the response to vaccination.¹

B group vitamins
B vitamins are water-soluble vitamins and work as part of coenzymes.² B vitamins are generally involved in intestinal immune regulation, thus contributing to gut barrier function.¹ Vitamins B6 and B12 and folate (Vitamin B9) all support the activity of natural killer cells and CD8+ cytotoxic T lymphocytes, effects which would be important in antiviral defence.¹ Lack of vitamin B6 deficiency causes thymus and spleen atrophy, low blood T lymphocyte numbers, and impaired lymphocyte proliferation and T lymphocyte-mediated immune responses,¹ while vitamin B12 deficiency decreases phagocytic** and bacterial killing capacity of neutrophils. In general, shortage of B vitamins weakens the host immune response.

Other B vitamins also has their special functions.1 Vitamin B2 (riboflavin) and UV light effectively reduced the amount of MERS-CoV in human plasma products.^2,3 Vitamin B3 (nicotinamide) could enhance the killing of Staphylococcus aureus (bacteria which often cause skin infections, pneumonia, heart valve infections, and bone infections). Moreover, lung injury during mechanical ventilation is usually seen in the severe cases of COVID-19 who need ventilators to get oxygen into body. Vitamin B3 treatment to these patients has a strong anti-inflammatory effect as it significantly inhibits neutrophil infiltration into the lungs.² Neutrophil infiltration in inflamed lung causes damage to the lung, and is a hallmark of Acute Respiratory Distress Syndrome in severe COVID-19 cases.

Vitamin C
Vitamin C is involved in collagen biosynthesis in connective tissues and is important for maintaining epithelial integrity (tissue in glands and linings).***^1,2

Its roles in immunity include leucocyte migration to sites of infection, phagocytosis** and bacterial killing, natural killer cell activity, T lymphocyte function (especially of CD8+ cytotoxic T lymphocytes) and antibody production1 (similar to the function of vitamin A).

Vitamin C supplementation has been shown to decrease the duration and severity of upper respiratory tract infections such as the common cold.¹ People deficient in vitamin C are susceptible to severe respiratory infections such as pneumonia.¹ This suggests that vitamin C might prevent the susceptibility to lower respiratory tract infections. Furthermore, vitamin C may also protect against infection caused by a coronavirus, as vitamin C increased the resistance of cultures of chick embryo tracheal organ to avian coronavirus infection.² As COVID-19 is related to lower respiratory tract infection, the Chinese researchers of a review article even suggest vitamin C could be one of the choices for COVID-19 treatment.²

Vitamin D
Vitamin D receptors are found in most immune cells. Vitamin D stimulates the maturation of many immune cells, and enhances epithelial integrity. Vitamin D also induces antimicrobial peptide synthesis in epithelial cells and macrophages, directly enhancing host defence.¹ Moreover, vitamin D increases phagocytosis, superoxide^# production and bacterial killing by innate immune cells.¹

A study from Taiwan found that people with vitamin D deficiency has lower antibody response, after vaccination with influenza A virus subtype H3N2 and B strain, than the group of people with normal vitamin D levels.¹ Studies using data from British and American populations suggested that vitamin D levels is inversely correlated with respiratory infection. This means the lower the vitamin D levels, the higher the risk of viral respiratory tract infection.¹

Vitamin D can be synthesized in our body with the help of sunlight. Summer is the time with sufficient sunlight, but over a year it is only a short time, so a high proportion of healthy adults in the UK are reported to have low levels of vitamin D. Moreover, the reduced outdoor journies due to the COVID-19 pandemic, further decreases the chance of people to absorb sunlight. Therefore, in addition to absorbing vitamin D from food, vitamin D deficient patients in the UK are usually prescribed vitamin D supplements by a GP. Meanwhile, a study in Japan found that supplementation of Japanese schoolchildren with vitamin D for 4 months during winter reduces the risk of influenza A by about 40%.¹

Vitamin E
Vitamin E is a lipid-soluble antioxidant that plays an important role in reducing oxidative stress through binding to free radicals.²

Vitamin E also plays a role in immune response and enhances antibody production.¹ The effect of vitamin E is especially obvious in healthy adults over 60 years of age. Research found a positive association between plasma vitamin E and cell-mediated immune response, and a negative association between plasma vitamin E and the risk of infections in this age group.¹ Studies by the Nutrition Research Center on Ageing at Tufts University in Boston demonstrated that vitamin E supplementation at high doses (800 mg/day) enhanced T helper 1 cell-mediated immunity (lymphocyte proliferation and IL-2 production), and improved vaccination response to the hepatitis B virus.¹ The same research group also reported that a daily intake of vitamin E supplement (135mg/day) for a year decreased upper respiratory tract infections, particularly the common cold, in elderly residents of a nursing home.¹ A study from Spain provided further evidence that supplementation of older adults with vitamin E improved their immunity defences.¹

Information on other nutrients to protect ourselves from infectious diseases will be presented in my next blog post.



*Epithelial tissue covers most of the external and internal surfaces of the body and its organs. These tissues serve as the first line of defence against inorganic, organic, and microbial intruders. Epithelial cells are the main cell type of these tissues.⁴
**Phagocytosis is a process of ingesting harmful foreign particles, bacteria, and dead or dying cells.
***Epithelial cells are the main cell type of epithelial tissues, which cover most of the external and internal surfaces of the body and its organs.⁴ Epithelial integrity is very important as a first line of defence against inorganic, organic, and microbial intruders.
^#Superoxide is a reactive oxygen species. It is generated by the immune system to kill invading pathogens in oxygen-dependent killing mechanisms.




References
1. P.C. Calder. Nutrition, immunity and COVID-19. Review. BMJ Nutrition, Prevention & Health. 2020, May 20;3(1):74-92.
2. L. Zhang, and Y. Liu. Potential interventions for novel coronavirus in China: A systematic review. Journal of Medical Virology, 2020, May 92(5):479-490.
3. S.D. Keil, R. Bowen, and S. Marschner. Inactivation of Middle East Respiratory Syndrome coronavirus (MERS-CoV) in plasma products using a riboflavin-based and ultraviolet light-based photochemical treatment. Transfusion. 2016;56:2948-2952.
4. J. Gunther, & H-M. Seyfert. The first line of defence: insights into mechanisms and relevance of phagocytosis in epithelial cells. Semin Immunopathol. 2018; 40(6): 555–565.

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.



References
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/

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.



References
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

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.

Conclusion
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.

References
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

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.

References
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.

Coronavirus (39) India is the world's biggest supplier of vaccines

Coronavirus (39) India is the world’s biggest vaccine supplier
For the last couple of weeks, reports of the second wave of COVID-19 in India have caught the attention of the whole world. The daily figures rose to 379,459 new confirmed cases and 3,647 deaths due to COVID-19 yesterday in India¹ and are expected to continue to rise for another two weeks, with a peak of nearly five hundred thousand new cases a day and more than 5000 deaths per day due to COVID-19 by mid-May.²

The world is now more connected than before, so this wave of COVID-19 in India will definitely affect the world’s economy, as India is the sixth largest economy in the world.³ Moreover, mutations of the virus may evolve every time the virus is passed on, so the higher the number of cases of infection, the higher the chance of a new variant emerging with higher transmissibility and/or higher resistance to the currently-available vaccines and therapies against COVID-19.

However, as the crisis is hitting India, the news reports also showed us something we might not have known before: India is the world’s biggest supplier of vaccines.⁴ You might be interested to know more about the vaccine industry in India and how that industry is involved in manufacturing vaccines against COVID-19. Let us have a look at this issue in this blog post.

India is the world’s biggest supplier of vaccines
The seven largest vaccine manufacturers in India have an installed capacity to manufacture a total of 8.2 billion doses of different vaccines per year.⁵ The first two largest vaccine manufacturers in India can already produce about 2.5 million doses a day.⁶ These vaccine manufacturers play a very important role in providing vaccines against COVID-19 worldwide.

Serum Institute of India (SII): the largest vaccine manufacturer in India
The Serum Institute of India (SII) is based in Pune and was founded in 1966 by Dr. Cyrus Poonawalla. According to the company’s website, it is the world's largest vaccine manufacturer by number of doses produced and sold globally. The company mainly produces traditional vaccines: its products include Polio vaccine, Diphtheria, Tetanus, Pertussis, Hib, BCG, r-Hepatitis B, Measles, Mumps and Rubella vaccines. The vaccines produced are being used in about 170 countries in the world in their national immunization programmes. Around 65% of the children in the world receive at least one vaccine manufactured by SII.⁷

Last June, SII obtained permission from AstraZeneca to manufacture Covishield, the COVID-19 vaccine which was co-developed by the University of Oxford and AstraZeneca. Under the agreement, the company will supply a total of one billion doses of Covishield for low- and middle-income countries. The company was expected to produce 100 million doses of Covishield per month.⁸

However, there was a fire at one of its facilities in January. Moreover, due to the surge in number of domestic COVID-19 cases, the Indian government started halting the exports of Covishield in March. Only 64 million dose of Covishield were exported before the halt in exports, 28 million of which went to COVAX, an organization co-led by GAVI (a global vaccine alliance), the Coalition for Epidemic Preparedness Innovations and WHO, one of the aims of which is to guarantee fair and equitable delivery of COVID-19 vaccines to poorer countries.⁸ This delayed planned deliveries of Covishield to 64 lower-income countries through COVAX.

In addition to Covishield, SII is also set to launch the production of millions of a protein vaccine, Covovax, developed by Novavax.⁹ The company’s CEO, Adar Poonawalla, said on Twitter that the vaccine is expected to be produced by September 2021. The company has initiated the Phase II and Phase III bridging trials for this vaccine.⁹

Bharat Biotech: the second largest vaccine manufacturer in India
The second largest vaccine manufacturer in India is Bharat Biotech. It was found in 1996 and is currently based in Hyderabad. The company owns over 160 patents and its products are used in over 123 countries. Since its establishment, the company has delivered over 4 billion vaccine doses worldwide. Its key focus is to develop and provide vaccines and therapeutics to the developing world.¹⁰

Since the beginning of the pandemic last year, Bharat Biotech collaborated with the Indian Council of Medical Research to develop an inactivated vaccine, Covaxin, against COVID-19. The company was given permission in January 2021 by the Indian government for emergency use of Covaxin. It is expected the company can make 12.5 million doses each month.⁸

Bharat Biotech is also conducting clinical trials for a intranasal viral vectored vaccine against COVID-19. The chairman of the company, Krishna Ella, expected that the vaccine could be available to the market by June this year if a protocol for all phases of clinical trials is clearly defined by the Indian government. If the company obtains emergency use approval from the government, he expected that the company can produce more than 1 billion doses.⁵

Other vaccine manufacturers in India
Besides the two biggest vaccine manufacturers, the other large vaccine manufacturers in India also fully participate in the campaign to manufacture vaccines against COVID-19. Biological E., another vaccine manufacturer based in Hyderabad, has signed a contract with Johnson & Johnson to produce 600 million doses of Ad26.COV2.S, a one-shot, adenovirus-vectored vaccine which has been approved to be used in the US.⁵

Moreover, Biological E. also cooperates with US organizations to develop an additional vaccine against COVID-19, a recombinant protein-subunit vaccine including antigen developed by Texas Children’s Hospital Center for Vaccine Development and advanced adjuvant CpG 1018TM from Dynavax. Biological E. announced on 24th April that it has successfully completed the Phase I/II clinical trial of this COVID-19 vaccine candidate in India and received approval to start the Phase III clinical trial from the Central Drugs Standard Control Organization- Subject Expert Committee.¹¹

Biological E. was founded in 1953 as the first private-sector biological products company in India and the first pharmaceutical company in Southern India. It develops, manufactures and supplies vaccines and therapeutics. Its vaccine products are sold to over 100 countries.¹¹

In addition, Dr. Reddy’s Laboratories, together with Panacea Biotech, Stelis Biopharm, Gland Pharma and Virchow Biotech, are about to produce an adenovirus vaccine, Sputnik V from Russia, for domestic use since the approval of its restricted use by the Indian government on the 12th of this month. It is expected that 850 million doses of Sputnik V per year could be produced from these vaccine manufacturers.⁵

Other than manufacturing COVID-19 vaccines that were developed elsewhere, there are several vaccine companies in India that developed COVID-19 vaccines by themselves, although most of them are currently far away from being launched. Among the COVID-19 vaccines undergoing clinical trials, a DNA plasmid-based vaccine, ZyCov-D, developed by Ahmedabad-based company Zydus Cadila, is in Phase 3 trials, and the initial data from the study is expected to be ready by May 2021.^12,13 The production of the ZyCoV-D vaccine has started with a yearly capacity of 240 million doses. It is expected to get emergency use authorization in May or June.¹⁴

Hopefully with the production of different COVID-19 vaccines by the vaccine manufacturers in India, and the ease of the export ban of raw material for vaccines from the US, the production of COVID-19 vaccines in India could be ramped up to its full capacity to provide as much vaccine as possible in time to alleviate the dire situation in India.



References
1. https://www.worldometers.info/coronavirus/country/india/
2. IIT scientists revise prediction on when COVID cases could peak in India. Mint, 6 Apr 2021. https://www.livemint.com/news/india/iit-scientists-revise-prediction-on-when-covid-cases-could-peak-in-india-11619437014161.html
3. "World Economic Outlook Database, April 2021". IMF.org. International Monetary Fund. April 2021. Retrieved 6 April 2021.
4. Why India's Covid crisis matters to the whole world. By Rebecca Morelle. BBC news, 28th April, 2021. https://www.bbc.co.uk/news/world-asia-india-56907007
5. How much vaccine can India make? And the catch...By Rai Vinaykumar. Business Today, April 14, 2021. https://www.businesstoday.in/coronavirus/after-launching-how-much-vaccine-can-india-make-and-the-catch/story/436474.html
6. India’s vaccine crisis is a warning to the world. By Grace Browne. WIRED, 29 April, 2021. https://www.wired.co.uk/article/india-vaccine-production
7. Serum Institute of India website. https://www.seruminstitute.com/about_us.php
8. India’s COVID-vaccine woes — by the numbers. How an explosion of coronavirus cases in India is putting global vaccine supplies at risk. T.V. Padma, Nature news, 15 April, 2021. https://www.nature.com/articles/d41586-021-00996-y
9. Serum Institute to delay launch of Novavax vaccine in India. Pharmaceutical Technology, 29 Mar 2021. https://www.pharmaceutical-technology.com/news/serum-institute-novavax-vaccine/
10. Bharat Biotech website. https://www.bharatbiotech.com
11. Biological E. Limited gets CDSCO nod to start Phase III clinical trial of its COVID-19 vaccine candidate. Biological E. press release, April 24, 2021. https://www.biologicale.com/news.html
12. DBT-BIRAC supported indigenously developed DNA vaccine candidate by Zydus Cadila, approved for Phase III clinical trials. pib.gov.in. Press Information Bureau, 3 January 2021.
13. Cadila Healthcare testing two-shot regimen for ZyCoV-D, data likely by May. By Das, Sohini. Business Standard, 22 April 2021. https://www.business-standard.com/article/current-affairs/cadila-healthcare-testing-two-shot-regimen-for-zycov-d-data-likely-by-may-121042200011_1.html
14. Cadila Healthcare starts production of Covid vaccine candidate. Mint news, 27 April 2021. https://www.livemint.com/companies/news/cadila-healthcare-starts-production-of-covid-vaccine-candidate-11619244017749.html