Contact Hours: 2
This educational activity is credited for 2 contact hours at completion of the activity.
The purpose of this course is to provide an up-to-date, in-depth overview of the COVID vaccines currently available. **Information on COVID-19 and vaccine availability is continuously evolving, and this course provides the most recent information that was available in July 2022.
Understanding the epidemiology of SARS-CoV-2 variants and the effectiveness of existing vaccines against them is essential to guide vaccination policies and the development of new vaccines. This course provides an up-to-date, in-depth overview of the COVID vaccines and their effectiveness. **Information on COVID-19 and vaccine availability is continuously evolving, and this course provides the most recent information that was available in July 2022.
Upon completion of the independent study, the learner will be able to:
- Review vaccine types readily available to the public
- Understand how vaccines work
- Understand the efficacy and side effects associated with vaccines
- Explain vaccine considerations in special populations
- Summarize post-vaccine administration precautions
This activity has been planned and implemented in accordance with the policies of FastCEForLess.com. If you want to review our policy, click here.
Fast CE For Less, Inc. and its authors have no disclosures. There is no commercial support.
|Adenovirus||Any of a group of DNA viruses first discovered in adenoid tissue, most of which cause respiratory diseases.|
|Covid-19||An acute disease in humans caused by a coronavirus, which is characterized mainly by fever and cough and is capable of progressing to severe symptoms and in some cases death, especially in older people and those with underlying health conditions.|
|Inactivated Virus||Commercially prepared vaccines against various virus infections|
|mRNA||Messenger RNA (abbreviated mRNA) is a type of single-stranded RNA involved in protein synthesis.|
|Nucleic Acid||A complex organic substance present in living cells, especially DNA or RNA, whose molecules consist of many nucleotides linked in a long chain.|
|Peptide||A compound consisting of two or more amino acids linked in a chain, the carboxyl group of each acid being joined to the amino group of the next by a bond of the type.|
|Protein Subunit Vaccines||Subunit vaccines contain fragments of protein and/or polysaccharide from the pathogen, which have been carefully studied to identify which combinations of these molecules are likely to produce a strong and effective immune response. By restricting the immune system’s access to the pathogen in this way, the risk of side effects is minimized.|
|Recombinant Designed Proteins||A protein encoded by a gene, recombinant DNA, which has been cloned in a system that supports expression of the gene and translation of messenger RNA.|
|Vaccine||A substance used to stimulate the production of antibodies and provide immunity against one or several diseases, prepared from the causative agent of a disease, its products, or a synthetic substitute, treated to act as an antigen without inducing the disease|
|Viral vector||Viral vector is the most effective means of gene transfer to modify specific cell type or tissue and can be manipulated to express therapeutic genes.|
Globally, as of July 2022, there have been over 5 ½ million confirmed cases of COVID-19, including more than 6 million deaths reported to the World Health Organization (WHO), as well as over 12 million vaccine doses that have been administered.11 The pandemic completely changed the outlook of the world, and the endpoint can only be herd immunity or the development of an effective vaccine.5
The COVID-19 pandemic can be characterized by the distribution of highly effective vaccines and the serial emergence of new SARS-CoV-2 genetic variants.1 Vaccines have shown short-term effectiveness with respect to symptomatic and asymptomatic SARS-CoV-2 infection, the severity of COVID-19, and secondary transmission.2 However, the long-term duration of vaccine protection remains uncertain.2
Multiple vaccine types, such as a peptide, virus-like particle, viral vectors (replicating and nonreplicating), nucleic acids (DNA or RNA), live attenuated virus, recombinant designed proteins, and inactivated virus, are currently under expansion, and a small number of vaccines have progressed into clinical trials. Among these, pharmaceutical companies like Pfizer and Moderna have mass-produced and administered vaccination to the public.5
Understanding the epidemiology of SARS-CoV-2 variants and the effectiveness of existing vaccines against them is essential to guide vaccination policies and the development of new vaccines.1 Thus, this course will focus on the most critical vaccines developed for COVID-19 up-to-date and their effectiveness.
Before we delve into the topic, we first need to understand how vaccines work. A vaccine works by training the immune system to recognize and combat pathogens like viruses or bacteria. For this, certain molecules from the pathogen must be introduced into the body to trigger an immune response.6
These molecules are called antigens and are present in all viruses and bacteria. By injecting these antigens into the body, the immune system can learn to recognize them as hostile invaders, produce antibodies, and remember them. If the bacteria or virus reappears, the immune system will immediately recognize the antigens and attack aggressively before the pathogen can spread and cause sickness.6
For COVID-19, a vaccine that elicits the production of S protein neutralizing antibodies in the vaccinated subjects is the program’s primary aim.7 Studies have revealed that there is limited to no cross-neutralization between the sera of SARS-CoV and SARS-CoV-2, indicating that recovery from one infection may not offer protection against the other.7
Viruses have the ability to mutate constantly and lead to variants. Some variants emerge and are of concern, while some simply disappear. Most viral mutations have a limited impact on the viruses’ ability to infect, replicate, escape host immunity, and transmit; however, certain mutations can give a viral strain a competitive advantage and, through natural selection, give it the ability to become dominant.12 The current method of identifying variants relies on the use of genomic testing such as whole genome sequencing, partial S gene sequencing, or assays based on nucleic acid amplification. 12
As of January 2022, the WHO reported five variants of concern, two variants of interest, and three variants under monitoring. 12 Among them, the variants of concern are alpha (b.1.7), beta (b.1.351), gamma (p.1), delta (b.1.617.2), and omicron (b.1.1.529). 12
As stated above, there are multiple COVID-19 vaccine types available. Different types of vaccines work in different ways to offer protection to the virus variants. However, with all types of vaccines, the body is left with a supply of “memory” T-lymphocytes and B-lymphocytes that will remember how to fight the virus in the future.8
The body typically takes a few weeks after vaccination to produce T-lymphocytes and B-lymphocytes. Therefore, it is possible that a person could be infected with COVID-19 just before or just after vaccination because the vaccine didn’t have enough time to build immunity. You might also develop symptoms like fever, which is normal in building immunity.8
Getting a COVID-19 vaccine is a safer and more reliable way to build protection and immunity and create an antibody response without having to experience severe illness or post-COVID symptoms.8 There are many other benefits of COVID-19 vaccines, including:
- Prevent infection: Based on randomized controlled trials, the immunization achieved from Pfizer and Moderna vaccines protected a remarkably high percentage (greater than 90%) of the individuals developing a symptomatic infection, and to a lesser extent, from asymptomatic infection too.9 Thus, these vaccines can prevent the transmission of the virus if administered and followed up properly.
- Highly effective: The CDC recommends everyone from the age of 6 months and older stay up to date with their vaccines. Vaccines can prevent severe illness, symptoms, hospitalization, and even death from COVID-19. However, the immune response to the COVID-19 vaccination may not be as strong as in people who are not immunocompromised.8
- Safe for children and adults: Extensive clinical trials were conducted, and no serious safety concerns were found for both children and adults. Moreover, serious side effects that could cause long-term health problems are rare after vaccination.8
- Help your unborn or newborn baby: Pregnant women can also get COVID-19 vaccines and help their unborn and newborn babies. Studies have shown that pregnant women that get the COVID-19 vaccines develop antibodies and pass them to their unborn or newborn baby through the placenta or breast milk.10
- Herd immunity: Countries with higher vaccination coverage had fewer COVID-19 cases and deaths per head of population, and the measured effectiveness in countries with high vaccine coverage was reassuringly large. Moreover, vaccination had a disproportionately large effect in countries with low and medium coverage. For instance, an incremental increase in coverage of only 20% (from very low to low) and 50% (from very low to medium) led to reductions in mortality of 60% and 75%, respectively.9
Many efforts have been directed toward the development of vaccines against COVID-19 to avert the pandemic, and most of the developing vaccine candidates have been using the S-protein of SARS-CoV-2.7 As of January 24, 2022, 33 approved vaccines are in use in 197 countries, with 10 vaccines approved for emergency use by the WHO.12
Here, we will overview the COVID-19 vaccines in use worldwide, categorized into types.
This type of vaccine contains material from the virus that causes COVID-19, which gives our cells instructions to make a harmless protein unique to the virus. After our cells make copies of the protein, they destroy the genetic material from the vaccine. Our bodies recognize that the protein should not be there and build T-lymphocytes and B-lymphocytes that will remember how to fight the virus that causes COVID-19 if we are infected in the future.8
The BNT162b2 vaccine (Comirnaty) is a lipid nanoparticle formulated, nucleoside-modified, mRNA vaccine encoding a modified SARS-CoV-2 S protein that was developed through a collaborative effort between Pfizer and BioNTech.12 This vaccine allows for the body to create an antibody response to neutralize the virus, which is dependent on the S protein for entry via the ACE2 receptor on type 2 alveolar cells.4
Following BNT162b2 vaccination, a response based on T helper 1 (Th1) cells is observed along with elevated levels of tumor necrosis factor α, interferon-gamma, and interleukin 2, compared with placebo.12
The mRNA-1273 vaccine (Spikevax) developed by Moderna is a lipid-nanoparticle encapsulated mRNA vaccine expressing the SARS-CoV-2 S protein that has been pre-fusion stabilized.12 This spike glycoprotein moderates host cell attachments. Hence, it is essential for viral entry, and thus, the primary vaccine target. The vaccine gives rise to a vigorous binding and neutralizing antibody response. This also includes CD4+ T-cell and CD8+ cytotoxic T-cell responses to eliminate the virus.4
Viral vectors provide an avenue for vaccines. The vectors may generally be classified as replicating or non-replicating vectors. Adenoviruses (Ads) are an example of vectors with both traits.4
ChAdOx1 nCoV-19 (Oxford-AstraZeneca)
The ChAdOx1 nCoV-19 vaccine (AZD1222, Vaxzevria) is a non-replicating vector of the chimpanzee adenovirus ChAdOx1, modified to encode the SARS-CoV-2 S protein and was developed through collaboration between the University of Oxford and AstraZeneca (Cambridge, UK).12
Following ChAdOx1 nCoV-19 vaccination, substantial antibody production (predominantly of IgG1 and IgG3 subclasses) is seen, as well as a Th1 cell response with increased expression of interferon γ and tumor necrosis factor α. One dose of the ChAdOx1 nCoV-19 vaccine has been shown to produce a neutralizing antibody response in 91% of participants, while a second dose has resulted in 100% of participants producing neutralizing antibodies.12
Ad26.COV.2.S (Johnson & Johnson)
The Ad26.COV.2.S vaccine is a non-replicating adenovirus vector modified to contain the SARS-CoV-2 S protein in a pre-fusion stabilized conformation and requires only one dose. This vector was developed from the recombinant human adenovirus type 26 by the Janssen pharmaceutical company Johnson & Johnson.12
The antibody directed against the S protein prevents invasion of the SARS-CoV-2 virus in type 2 alveolar cells of the lungs, thus reducing the severity and morbidity of the infection.4 Moreover, the Janssen vaccine is advantageous over the other candidate, as it is administered in only one dose, which reduces manufacturing costs.4
Protein Subunit Vaccines
The antigen’s appearance in its most steady and efficient conformation has been one of the difficulties of using the protein subunit vaccine. Virus-like particles (VLPs) are comprised of several protein molecules capable of self-assembling into nanostructures that surround the capsid proteins inside themselves upon recombinant expression.5 Moreover, VLPs lack a genome of their own; they deliver a degree of stability comparable to that of nonreplicating vectors, thereby verifying the safety of the subunit vaccines and the effectiveness of the live vaccines.5
This vaccine consists of a recombinant SARS-CoV-2 S protein nanoparticle combined with the adjuvant Matrix-M as a coformulation. It produces similar immune responses to those already discussed.12 Novavax directly injects a version of the spike protein, along with another ingredient that stimulates the immune system, into the body, producing antibodies and T-cells. (It injects a version of the spike protein that has been formulated in a laboratory as a nanoparticulate that does not have genetic material inside and cannot cause disease.)13
|Vaccine||Efficacy||Side Effects||Recommended Doses|
|BNT162b2/ Pfizer||Results showed 180 cases of SARS-CoV-2, 8 coming from the vaccinated group and 172 coming from the placebo group. This indicates a 95% effectiveness at preventing COVID-19 infections.4|
Well tolerated, with limited reactogenicity.12
|Redness and swelling at the injection site.12|
Common symptoms include fatigue, muscle pain, headache, and chills.12
No serious adverse events, but a large study of 884 828 pairs of individuals, split 1:1 based on vaccination status, found that BNT162b2 was associated with an increased risk of myocarditis, lymphadenopathy, appendicitis, and herpes zoster infection.12
|Two doses (30 µg, 0.3 mL each) intramuscularly (deltoid) with a recommended interval of 21–28 days between doses.12|
|mRNA-1273/Moderna||Under a study consisting of 30 420 medically stable adults with no known history of COVID-19 or high risk of severe COVID-19 infection, Moderna was found to have an efficacy of 94.1%.4||Mild injection pain lasting for 3 days.|
Fatigue, muscle pain, headache, chills, joint pain, and pain/reaction at the injection site.12
Serious adverse events, including allergic reaction and anaphylaxis, are rare but not inconceivable after mRNA-1273 vaccination.12
|Two doses (100 µg, 0.5 mL each) intramuscularly (deltoid) with a recommended interval of 28 days between doses.12|
|ChAdOx1 nCoV-19 (Oxford-AstraZeneca)||Efficacy of two doses of the vaccine was 70.4% and protection of 64.1% after at least one standard dose, against symptomatic disease.4||Mild and moderate itchiness, pain, redness, swelling, tenderness, and warmth are common local reactions.12 |
Chills, fatigue, fever, headache, muscle ache, and nausea are commonly reported systemic reactions after vaccination.12
Rare symptoms, including severe chest pain, nasal bleeding, and allergic reactions have also been reported after vaccination.12
|Two doses (0.5 mL each) intramuscularly (deltoid) with a recommended interval window of 8 to 12 weeks.12|
|Ad26.COV.2.S (Johnson & Johnson)||In a trial consisting of 43 783 seronegative participants, randomized into two similar groups into a 1:1 ratio with one receiving the placebo and the other receiving the vaccine, an efficiency of 66.9% was found.4||Headache, fatigue, and myalgia are the most common systemic reactions, while pain at the injection site is the most common local reaction after vaccination.12|
Associated with serious adverse events, such as allergic reactions and cerebral venous sinus thrombosis; however, these events are rare. 12
|One dose (0.5 mL) intramuscularly (deltoid).12|
|Novavax||According to an FDA summary, The vaccine was found to be 90% effective against mild, moderate, and severe disease in the company’s Phase 3 trial involving 30,000 participants ages 18 and older.13||The most reported side effects by vaccine recipients in the clinical trial were pain/tenderness, redness and swelling at the injection site, fatigue, muscle pain, headache, joint pain, nausea/vomiting, and fever.13 ||Two doses (0.5 mL) intramuscularly (deltoid) with a recommended interval of 3–4 weeks.12|
This section will discuss regulatory authorities’ approach to evaluating COVID-19 vaccines.
Vaccine manufacturers are legally obliged to follow defined standards in the data they provide, and their clinical research and manufacturing operations are subject to regulatory oversight. Either full or summary data from clinical trials is made available to regulators as part of vaccine evaluation.14
Each vaccine is thoroughly assessed for safety, efficacy, and quality to determine whether it can be approved for use. Regulators use available scientific evidence from preclinical laboratory research, human clinical trials, and manufacturing information to assess the benefits and risks of candidate vaccines. 14
Regulators seek expert advice from scientific advisory committees. These committees include experts in science, medicine (including infectious diseases), and public health and often include consumer and healthcare representatives.14
Safety evidence is essential to each regulatory submission for a COVID-19 vaccine. It is gathered during all phases of the vaccine development process. Robust assessment of safety is carried out in the clinical trials and submitted to regulators for review as part of the approval process.14
During this process:14
- Adverse events are examined and reported.
- Clinical trials are followed at least 2 months after participants receive their final vaccine dose for decisions made under emergency, provisional, or conditional approval processes.
- There will also be longer-term (for example, 1 to 2 years) follow-up of those who participated in the clinical trials of each vaccine.
- Regulators carefully review safety data from these longer-term trials and population studies as part of post-approval monitoring of safety.
- Any COVID-19 vaccine that receives regulatory authorization must be manufactured according to internationally accepted stringent regulatory standards of good manufacturing practices (GMP).14
- Regulators review data to confirm the manufacturing process at each production site is well controlled and consistent.14
- After approval, batches undergo evaluation by individual national regulatory authorities to ensure they meet national requirements.14
Companies must submit data from well-designed clinical trials to regulators to demonstrate that the vaccine prevents COVID-19.14
Clinical trials should include:14
- Populations in clinical trials should include a range of age groups and people with comorbidities.
- Given the disproportionate impact of COVID-19 on older people, COVID-19 vaccine clinical trials should include significant numbers of older participants.
Moreover, efficacy data should also include characterization of comparative immunogenicity profiles, including cell-mediated immunity, and comparative in vitro neutralization characterization against Variants of Concern.14
After approval, regulators conduct robust effectiveness monitoring as well as monitoring of safety and risk minimization activities. They need to continuously monitor vaccine safety to ensure that the benefits of the vaccine continue to outweigh the risks.14
Pregnant and recently pregnant women are more likely to get severely ill with COVID-19 compared to non-pregnant women.15 However, accumulating data provides scientific evidence of both the safety and effectiveness of COVID-19 vaccination in pregnancy. The CDC strongly recommends COVID-19 vaccination either before or during pregnancy because the benefits of vaccination for both pregnant persons and their fetus/infant outweigh known or potential risks.15
CDC reports have shown that breastfeeding women who have received mRNA COVID-19 vaccines have antibodies in their breast milk, which could help protect their babies.15
In most cases, people with allergies can easily get COVID-19 vaccines with the same adverse effects as anyone else, except for the following 2 exceptions:15
- People with a severe allergic reaction (anaphylaxis) to any component of either an mRNA vaccine or the Johnson & Johnson COVID-19 vaccine should NOT receive that vaccine.
- People with a severe allergic reaction (anaphylaxis) to any vaccine or injectable (intramuscular or intravenous) medication should consult with their health provider to assess risk prior to receiving the COVID-19 vaccine.
People with severe allergies require a 30-minute observation period after vaccination, while all others must be observed for 15 minutes. Vaccine clinics have safety protocols in place to respond to any adverse reactions.15
However, pregnant individuals or individuals with allergies and autoimmune diseases should consult a healthcare professional before getting vaccinated to discuss symptoms and adverse effects and the care needed following vaccination.
COVID-19 vaccines show excellent efficacy in clinical trials and effectiveness in real-world data, but some people still become infected with SARS-CoV-2 after vaccination.16 We are going to focus on a real-world case study conducted in the UK to identify risk factors for post-vaccination SARS-CoV-2 infection and describe the characteristics of the post-vaccination illness.
The case study involved adult (≥18 years) users of the COVID Symptom Study mobile phone app. For the risk factor analysis, cases had received a first or second dose of a COVID-19 vaccine between Dec 8, 2020, and July 4, 2021; had either a positive COVID-19 test at least 14 days after their first vaccination (but before their second; cases 1) or a positive test at least 7 days after their second vaccination (cases 2); and had no positive test before vaccination.16
Two control groups were selected (who also had not tested positive for SARS-CoV-2 before vaccination): users reporting a negative test at least 14 days after their first vaccination but before their second (controls 1) and users reporting a negative test at least 7 days after their second vaccination (controls 2). Controls 1 and 2 were matched (1:1) with cases 1 and 2, respectively, by the date of the post-vaccination test, health-care worker status, and sex. In the disease profile analysis, we sub-selected participants from cases 1 and 2 who had used the app for at least 14 consecutive days after testing positive for SARS-CoV-2 (cases 3 and 4, respectively).16
Controls 3 and controls 4 were unvaccinated participants reporting a positive SARS-CoV-2 test who had used the app for at least 14 consecutive days after the test and were matched (1:1) with cases 3 and 4, respectively, by the date of the positive test, health-care worker status, sex, body mass index (BMI), and age.16
In the risk factor analysis,16
- Frailty was associated with post-vaccination infection in older adults (≥60 years) after their first vaccine dose.
- Individuals living in highly deprived areas had increased odds of post-vaccination infection following their first vaccine dose.
- Individuals without obesity (BMI <30 kg/m2) had lower odds of infection following their first vaccine dose.
For the disease profile analysis,
- 3825 users from cases 1 were included in cases 3, and 906 users from cases 2 were included in cases 4.
Vaccination (compared with no vaccination) was associated with reduced odds of hospitalization or having more than five symptoms in the first week of illness following the first or second dose and long-duration (≥28 days) symptoms following the second dose. Almost all symptoms were reported less frequently in infected vaccinated individuals than in infected unvaccinated individuals, and vaccinated participants were more likely to be completely asymptomatic, especially if they were 60 years or older.16
To minimize SARS-CoV-2 infection post-vaccination:16
- Strong emphasis on booster vaccinations
- Not relaxing physical distancing and other personal protective measures in the post-vaccination era, especially among older adults and people living in deprived areas.
The treatment and management of COVID-19 is a continually evolving topic; however, health authorities have published and continue to update guidelines and recommendations for treating COVID-19.12
COVID-19 remains prevalent and life-threatening. Although the rollout of vaccines has been successful, attaining a high global vaccination coverage and ensuring that all healthcare systems have the capacity to cope with seasonal waves is essential. With the omicron variant highly prevalent, we must continue to learn, develop therapeutics, and remain vigilant to new variants of concern.12
- Lauring AS, Tenforde MW, Chappell JD, et al. Clinical severity of, and effectiveness of mRNA vaccines against, COVID-19 from omicron, delta, and alpha SARS-CoV-2 variants in the United States: prospective observational study. BMJ. Published online March 9, 2022:e069761. doi:10.1136/bmj-2021-069761
- Hall V, Foulkes S, Insalata F, et al. Protection against SARS-CoV-2 after COVID-19 Vaccination and Previous Infection. New England Journal of Medicine. Published online February 16, 2022. doi:10.1056/nejmoa2118691
- Eyre DW, Taylor D, Purver M, et al. Effect of COVID-19 Vaccination on Transmission of Alpha and Delta Variants. New England Journal of Medicine. Published online January 5, 2022. doi:10.1056/nejmoa2116597
- Francis AI, Ghany S, Gilkes T, Umakanthan S. Review of COVID-19 vaccine subtypes, efficacy and geographical distributions. Postgraduate Medical Journal. Published online August 6, 2021:postgradmedj-2021-140654. doi:10.1136/postgradmedj-2021-140654
- Shahcheraghi SH, Ayatollahi J, Aljabali AA, et al. An overview of vaccine development for COVID-19. Therapeutic Delivery. 2021;12(3):235-244. doi:10.4155/tde-2020-0129
- PublicHealth. How Vaccines Work | PublicHealth.org. PublicHealth.org. Published 2011. https://www.publichealth.org/public-awareness/understanding-vaccines/vaccines-work/
- Kaur SP, Gupta V. COVID-19 Vaccine: A comprehensive status report. Virus Research. 2020;288:198114. doi:10.1016/j.virusres.2020.198114
- Centers for Disease Control and Prevention. Benefits of Getting a COVID-19 Vaccine. Centers for Disease Control and Prevention. Published 2021. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/vaccine-benefits.html
- Dye C. The benefits of large scale COVID-19 vaccination. BMJ. 2022;377:o867. doi:10.1136/bmj.o867
- MU Health Care. What Are the Benefits of Getting the COVID-19 Vaccine? www.muhealth.org. Published 2021. https://www.muhealth.org/our-stories/what-are-benefits-getting-COVID-19-vaccine
- World Health Organization. WHO COVID-19 dashboard. World Health Organization. Published 2022. https://covid19.who.int/
- Young M, Crook H, Scott J, Edison P. COVID-19: virology, variants, and vaccines. BMJ Medicine. 2022;1(1). doi:10.1136/bmjmed-2021-000040
- Novavax’s COVID-19 Vaccine: Your Questions Answered. Yale Medicine. Accessed July 27, 2022. https://www.yalemedicine.org/news/novavax-covid-vaccine
- WHO. Statement for healthcare professionals: How COVID-19 vaccines are regulated for safety and effectiveness. www.who.int. Published May 17, 2022. https://www.who.int/news/item/17-05-2022-statement-for-healthcare-professionals-how-COVID-19-vaccines-are-regulated-for-safety-and-effectiveness
- Information for Special Populations and the COVID-19 vaccine | Yale Health. yalehealth.yale.edu. Published October 4, 2021. https://yalehealth.yale.edu/yale-COVID-19-vaccine-program/information-special-populations-and-COVID-19-vaccine
- Antonelli M, Penfold RS, Merino J, et al. Risk factors and disease profile of post-vaccination SARS-CoV-2 infection in UK users of the COVID Symptom Study app: a prospective, community-based, nested, case-control study. The Lancet Infectious Diseases. 2021;22(1). doi:10.1016/s1473-3099(21)00460-6