The role of vaccines in a pandemic

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Herd immunity

Herd or community immunity provides protection from infection, particularly for vulnerable individuals within a population, and is ideally achieved through mass vaccination programs.[1]

Herd immunity is defined as the indirect protection of vulnerable and other individuals that occurs when a sufficiently large proportion of infection-specific immune individuals (i.e., vaccinated individuals or convalesced patients) exists in a population.[1]

  • The average number of secondary cases of an infectious disease that one case would generate in a completely susceptible population is known as the basic reproduction number (R0).
  • The herd immunity threshold is the level needed to stop this transmission.[1],[2]
  • Although current estimates differ by region based on variabilities in infection rates and implementation of transmission prevention measures (such as mask wearing and social gathering restrictions), it is estimated that a minimum herd immunity threshold of 60-80% will be needed in order to begin to observe a decline in SARS-CoV-2 infections.[1],[3],[4]

Herd immunity breaks the chain of transmission.[5]
It can be achieved through natural infection and/or mass vaccination.[1]

Naive population: Outbreak quickly emerges

Herd immunity*: Virus fails to spread and persist in the population

Successful transmission

Unsuccessful transmission

Infected

Immune

Susceptible individual

Susceptible but indirectly protected individual

* 70% of the population is immune

Adapted from Randolph, HE Immunity 2020[5]

Without vaccination, herd immunity can occur naturally over time if infected individuals recover and develop adaptive immunity[1] via T cells, B cells or antibodies[6] that provide sterilizing immunity – i.e., the host could no longer carry or transmit the infection.[5] This process can be uncontrolled, allowing the virus to spread with no intervention, or via a controlled natural infection route, where distancing measures are used to target the infection of low-risk individuals in the population.[7]

If herd immunity is achieved without vaccination (i.e., natural immunity), it could come at the cost of significant morbidity and mortality in any given population.[1],[7]

  • The case fatality rate (CFR) is the percentage of deaths caused by a specific disease in a specific range of time.[1],[8] The overall global CFR for COVID-19 is unclear due to differences in implementing intervention measures to limit transmission, public access to testing, and case reporting methods between countries. However, values currently range from 29.13% in Yemen, 9.87% in Mexico, 7.46% in Ecuador, 6.02% in Sudan, 5.38% in China, 4.40% in the UK, 4.20% in Canada, 3.28% in Australia, 2.74% in Turkey, 2.46% in the U.S., and 1.88% in Germany (as of November 4, 2020).
  • Approximately 30 million deaths are estimated if herd immunity to SARS-CoV-2 is achieved without the implementation of mass vaccination programs across the globe.[1]

Overall, this highlights the potential importance of achieving herd immunity through mass vaccination versus through natural infection.[1],[8]

  • However, vaccines must not only be effective, but vaccination programs must also have broad uptake to ensure that those who cannot be directly vaccinated will derive indirect herd protection.[5]
  • In addition, the durability of immune memory is a critical factor in determining sustained herd immunity, and to date immunity to seasonal coronaviruses has been short-lived.[5],[9]

Given that SARS-CoV-2 is now a global pathogen, it is possible that it will settle into a pattern of seasonal variation as observed with the other beta coronaviruses.[7]

Although mass vaccination programs are the current focus of herd immunity strategies (in concert with other intervention measures such as wearing masks, physical distancing, and emphasis on hygiene and cleaning), if SARS-CoV-2 becomes endemic, future approaches may transition to seasonal vaccination programs (similar to those for influenza virus).[1],[2],[7],[10]

Vaccination for prevention of diseases on individual and
population-level

Vaccination is a well-tolerated, effective, and cost-saving method proven to prevent diseases in individuals as well as population-level disease-specific outbreaks.[11]

Vaccines prevent diseases in individuals (including potentially serious illness, complications, and death) by training the immune system to respond to pathogens/antigens in a controlled manner. As a result, vaccination limits the symptomology and complications that would normally be experienced during a natural course of infectious disease.[11] In turn, population-level disease-specific outbreaks can be prevented when enough individuals are vaccinated against that specific disease to create herd immunity.[11]

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Vaccines have been utilized successfully since the late 1800s. Infectious diseases that are currently preventable by vaccination include:[11]

  • Cholera
  • Diphtheria
  • Hepatitis B
  • Influenza
  • Measles
  • Mumps
  • Pertussis (whooping cough)
  • Polio
  • Rabies
  • Rotavirus
  • Rubella
  • Tetanus
  • Typhoid
  • Varicella (chickenpox; varicella-zoster virus)
  • Cervical cancer (linked to specific strains of human papillomavirus)

One example of a global mass vaccination program is that for polio,[12] which has resulted in the eradication of this disease since 1979 in the United States[13] and since 2012 worldwide.[12] Mass vaccination programs for the other diseases listed above have resulted in the significant decline (and near eradication) above their prevalence over the years. However, outbreaks of some of these diseases (e.g., measles and pertussis in Germany[14],[15] and elsewhere[14]-[16]) have been seen in recent years due to vaccine refusal by some subpopulations.

Vaccines leverage the body’s natural immune defenses by providing the stimulus for the immune system to identify specific pathogenic antigens and then mount an appropriate antibody and cellular response against those antigens.[5] In addition to this response, immune memory is generated. This is critical to allow the body to quickly and effectively fight against future exposure with minimal to no symptomology.[11]

Common side effects to vaccination are generally mild and limited, and they may include temporary discomfort at the site of administration (especially if injected) or temporary low-grade fever.[11] More serious side effects have been documented but occur rarely.

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© Liderina - shutterstock.com

In addition, vaccines are a cost-effective public health intervention, as the up-front financial investment for a vaccine is counterbalanced by avoiding the direct and indirect medical and societal costs through disease prevention. These preventable costs may include:[17],[18]

  • Financial burden associated with infection treatment, complications, long-term sequelae (including impact on mental health and permanent disability), and hospitalization
  • Cost of travel and other special considerations, such as childcare or care for other family members
  • Loss of time and productivity at work and/or school
  • Loss of time for diagnoses and extra expense for treating further enhanced disease

Recommendations from German, EU, and other vaccination
committees

The European Centre for Disease Prevention and Control (ECDC) anticipates an initial shortage of vaccine and predicts that countries will need to identify priority groups for vaccination, with broad characterization to further categorize them into different priority tiers. A functioning vaccine is considered essential to containing the pandemic, in addition to current non-pharmaceutical interventions (such as physical distancing) and antivirals.[19]

The German Standing Committee on Vaccination (STIKO) recommends to first vaccinate persons above the age of 80 years as well as persons living in retirement and nursing homes. The STIKO also recommends the vaccination of healthcare personnel and persons working in nursing homes.[20]

The World Health Organization (WHO) Strategic Advisory Group of Experts on Immunization (SAGE) recommendations for COVID-19 similarly focus on the prioritization of vaccination for high-risk groups and provides a detailed “values framework” for fair vaccine distribution.[21]

The U.S Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) recommendations for COVID-19 currently emphasize the following goals for a limited COVID-19 vaccine supply:[22]

  • “Decrease death and serious disease as much as possible
  • Preserve functioning of society
  • Reduce the extra burden the disease is having on people already facing disparities
  • Increase the chance for everyone to enjoy health and well-being”

In addition to this, the CDC ACIP COVID-19 recommendations specify groups who should be prioritized for early vaccination in the case of limited COVID-19 vaccine supply. These are:[22]

  • “Healthcare personnel
  • Workers in essential and critical industries
  • People at high risk for severe COVID-19 disease due to underlying medical conditions
  • People 65 years and older”

Robust regulatory framework for COVID-19 vaccines[23]-[27]

The EMA states that COVID-19 vaccines are being developed following the same legal requirements for pharmaceutical quality, safety and efficacy as other medicines. The EMA’s pharmaceutical legislation ensures that vaccines are approved only after scientific evidence has demonstrated that their overall benefits outweigh their risks.[23] In view of the pandemic, the EMA and regulatory agencies in Europe are diverting resources to speed up processes and reduce timelines for the evaluation and authorization of COVID-19 vaccines.[23]

The U.S. FDA has rigorous scientific and regulatory processes in place to facilitate development and ensure the safety, effectiveness and quality of COVID-19 vaccines.[24] Guidance for Industry published in June 2020 gave recommendations on the data required to facilitate the clinical development and licensure of COVID-19 vaccines.[25]

  • COVID-19 vaccines licensed in the U.S. must meet the statutory and regulatory requirements for vaccine development and approval, including for quality, development, manufacture, and control.[25]
  • COVID-19 vaccine development may be accelerated based on knowledge gained from similar products manufactured with the same well-characterized platform technology, to the extent legally and scientifically permissible.[25]
  • As there are no accepted surrogate endpoints that are reasonably likely to predict clinical benefit of a COVID-19 vaccine, the goal of development programs should be to pursue traditional approval via direct evidence of vaccine safety and efficacy in protecting humans from SARS-CoV-2 infection and/or clinical disease.[25]

The Medicines & Healthcare products Regulatory Agency (MRHA) have announced regulatory flexibilities in the UK.[26],[27]

  • This includes expedited scientific advice, and rapid reviews of clinical trials applications to support manufacturers and researchers on potential treatments for COVID-19.[26]
  • A temporary authorization to supply an unlicensed vaccine could be given by the UK’s licensing authority under regulation 174 of the Human Medicines Regulations.[27] On December 2nd, 2020 the MHRA authorized BNT162b2 under these conditions.

The WHO target product profiles for COVID-19 vaccines

The WHO has developed “WHO Target Product Profiles for COVID-19 Vaccines,” a document that provides guidelines for vaccine researchers, developers, manufacturers, and funding agencies on preferred outbreak and long-term COVID-19 vaccine characteristics. These profiles include details on safety, efficacy, and accessibility considerations for low- and middle-income countries.[28]

  • The preferred safety/reactogenicity profile recommended in “WHO Target Product Profiles for COVID-19 Vaccines” should have “safety and reactogenicity sufficient to provide a highly favorable benefit/risk profile in the context of observed vaccine efficacy; with only mild, transient adverse events (AEs) related to vaccination and no serious AEs.” Additionally, the document specifies that there should be no contraindications, and the vaccine should be well tolerated and effective for use in individuals of all ages as well as pregnant and lactating women.[28]
  • Furthermore, the preferred efficacy profile recommended is “at least 70% efficacy (on population basis, with consistent results in the elderly),” with a preferred durability of protection of at least 1 year.[28]
  • Regarding accessibility considerations during outbreak conditions, WHO emphasizes the “capability to rapidly scale-up production at cost/dose that allows broad use, including in low- and middle-income countries (LMIC),” while in the long term, it recommends the “availability of sufficient doses at cost/dose that allows broad use, including in low- and middle-income countries.”[28]

The “ideal” COVID-19 vaccine candidate

Based on current immunological evidence, an ideal COVID-19 vaccine candidate will elicit a targeted anti-viral immune response including a TH1-biased cellular response, generation of neutralizing antibodies, and CD8 T cells.[9],[29]

As with any anti-viral vaccine, an ideal COVID-19 vaccine candidate will be designed to leverage the inherent biological processes of natural adaptive immune responses, including specificity to appropriate antigenic epitopes and induction of long-lasting immune memory.[9],[29]

  • The immunological memory (memory B cells and T cells) generated by a vaccine grants those vaccinated the ability to quickly respond to subsequent exposures to the same or similar pathogen and to eliminate the pathogen (in a fraction of the time of a natural infection) with no or minimal symptomology.[30]

Intramuscular injection of the vaccine will activate the innate immune system (i.e., dendritic cells (DCs) and other antigen-presenting cells (APCs)), stimulating further immune responses at the injection site (i.e., secretion of cytokines and recruitment of additional immune cells) and in the draining lymph nodes, where APCs activate some antigen-specific B cells and T cells.[29],[31]

The expressed antigenic protein is then processed into peptides, which are presented on major histocompatibility (MHC) class I and II molecules of APCs to CD8 and CD4 T cells, respectively, stimulating expansion of the immune response, including generation of neutralizing antibodies and cytotoxic T-cell responses, as well as production of memory B cells and T cells.[29],[31]

  • TH1 (T-helper 1) CD4 T cells secrete anti-viral cytokines (including IFN-g, TNF-a, TNF-B, and IL-2) which help activate B cells and CD8 T cells.[29]
  • Anti-viral neutralizing antibodies, produced and secreted by B cells after appropriate stimulation, are important for restricting productive infection by binding to free/unbound virus particles in the body and preventing their binding and entry into target cells.[29]
  • CD8 T cells (also known as cytotoxic T lymphocytes, CTLs) identify and eliminate virus-infected cells directly by their secretion of perforin and granzymes.[17] Perforin perforates the infected cell’s membrane, thus allowing for the entry of granzymes which enter the cell and stimulate the cell’s caspase cascade resulting in apoptosis/programmed cell death. CD8 T cells can also mediate other anti-viral effects (such as inhibition of viral entry and replication) through the secretion of IFN-g and TNF-a.[29],[31]

Adapted from Dong Y. et al., Signal Transduct Target Ther. 2020[33]

References

  1. Randolph HE, Barreiro LB. Immunity 2020;52:737–741.
  2. Global Virus Network. COVID-19 vs influenza: influenza vaccination amid COVID-19 pandemic. https://gvn.org/covid-19-vs-influenza-influenza-vaccination-amid-covid-19-pandemic/. Published September 11, 2020. Accessed November 26, 2020.
  3. Aguas R, et al. Herd immunity thresholds for SARS-CoV-2 estimated from unfolding epidemics. Preprint at medRxiv. https://www.medrxiv.org/content/10.1101/2020.07.23.20160762v3.full.pdf
  4. Gomes MGM, et al. Individual variation in susceptibility or exposure to SARS-CoV-2 lowers the herd immunity threshold. Preprint at medRxiv. https://www.medrxiv.org/content/10.1101/2020.04.27.20081893v3
  5. Omer SB, et al. JAMA 2020;324(20):2095–2096.
  6. InformedHealth. The innate and adaptive immune system. https://www.ncbi.nlm.nih.gov/books/NBK279396/ Published July 30, 2020. Accessed November 26, 2020.
  7. Marais BJ, Sorrell TC. Int J Infect Dis 2020;96:496–499.
  8. Centre for Evidence-Based Medicine website. Global Covid-19 case fatality rates. https://www.cebm.net/covid-19/global-covid-19-case-fatality-rates/. Country data updated November 4, 2020. Accessed November 26, 2020.
  9. Poland GA, et al. Lancet 2020;S0140-6736(20)32137–1.
  10. Altmann DM, et al. Lancet 2020;395:1527–1529.
  11. World Health Organization. Q&A on vaccines. https://www.who.int/vaccines/questions-and-answers/q-a-on-vaccines. Published August 26, 2019. Accessed November 26, 2020.
  12. World Health Organization. 10 facts on polio eradication. https://www.who.int/features/factfiles/polio/en/#:~:text=Type%202%20wild%20poliovirus%20was,in%20the%20world%20since%202012. Updated April 2017. Accessed November 26, 2020.
  13. Centers for Disease Control and Prevention. Polio elimination in the United States. https://www.cdc.gov/polio/what-is-polio/polio-us.html. Reviewed October 25, 2019. Accessed September 30, 2020.
  14. Holzmann H, et al. Med Microbiol Immunol 2016;205(3):201–208.
  15. Esposito S, et al. Front Immunol 2019;10:1344.
  16. Phadke VK, et al. JAMA 2016;315:1149–1158.
  17. Kim JJ. N Engl J Med 2011;365:1760–1761.
  18. Centers for Disease Control and Prevention. Vaccines for Children Program, VFC publications: supplement. https://www.cdc.gov/vaccines/programs/vfc/pubs/methods. Updated April 23, 2014. Accessed November 26, 2020.
  19. European Centre for Disease Prevention and Control. Key aspects regarding the introduction and prioritisation of COVID-19 vaccination in the EU/EEA and the UK. https://www.ecdc.europa.eu/en/publications-data/key-aspects-regarding-introduction-and-prioritisation-covid-19-vaccination. Published October 26, 2020. Accessed November 26, 2020.
  20. Robert Kock Institut. Vaccination recommendations by STIKO. https://www.rki.de/DE/Content/Infekt/EpidBull/Archiv/2021/Ausgaben/02_21.pdf?__blob=publicationFile. Accessed December 19, 2020.
  21. World Health Organization. WHO SAGE values framework for the allocation and prioritization of COVID-19 vaccination. https://apps.who.int/iris/bitstream/handle/10665/334299/WHO-2019-nCoV-SAGE_Framework-Allocation_and_prioritization-2020.1-eng.pdf. Published September 14, 2020. Accessed November 26, 2020.
  22. Centers for Disease Control and Prevention. How CDC is making COVID-19 vaccine recommendations. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations-process.html. Updated October 13, 2020. Accessed November 26, 2020.
  23. EMA. COVID-19 vaccines: development, evaluation, approval and monitoring. https://www.ema.europa.eu/en/human-regulatory/overview/public-health-threats/coronavirus-disease-covid-19/treatments-vaccines/covid-19-vaccines-development-evaluation-approval-monitoring Published. Accessed November 26, 2020.
  24. FDA. COVID-19 vaccines. https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/covid-19-vaccines#:~:text=FDA%20has%20rigorous%20scientific%20and,the%20prevention%20of%20COVID%2D19. Accessed November 26, 2020.
  25. FDA2. Development and Licensure of Vaccines to Prevent COVID-19 Guidance for Industry. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/development-and-licensure-vaccines-prevent-covid-19 Published June 2020. Accessed November 26, 2020.
  26. MRHA. Guidance: MHRA regulatory flexibilities resulting from coronavirus (COVID-19). https://www.gov.uk/guidance/mhra-regulatory-flexibilities-resulting-from-coronavirus-covid-19 Published August 4, 2020. Accessed November 26, 2020.
  27. MRHA. Consultation document: changes to Human Medicine Regulations to support the rollout of COVID-19 vaccines. https://www.gov.uk/government/consultations/distributing-vaccines-and-treatments-for-covid-19-and-flu/consultation-document-changes-to-human-medicine-regulations-to-support-the-rollout-of-covid-19-vaccines Published October 16, 2020. Accessed November 26, 2020.
  28. World Health Organization. WHO target product profiles for COVID-19 vaccines. https://www.who.int/blueprint/priority-diseases/key-action/WHO_Target_Product_Profiles_for_COVID-19_web.pdf. Published April 9, 2020. Accessed November 26, 2020.
  29. Siegrist C. Chapter 2: Vaccine immunology. In: Plotkin SA, Orenstein WA, Offit PA, editors. Plotkin’s Vaccines. 7th edition. Philadelphia, PA: Elsevier; 2017. Available from WHO website: https://www.who.int/immunization/documents/Elsevier_Vaccine_immunology.pdf. Accessed November 26, 2020.
  30. Janeway CA Jr, et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001. The importance of immunological memory in fixing adaptive immunity in the genome. https://www.ncbi.nlm.nih.gov/books/NBK27087/. Accessed November 26, 2020.
  31. Armbruster N, et al. Vaccines (Basel). 2019;7:132.
  32. Kang S, et al. Immune Netw 2018;18(5):e33.
  33. Dong Y. et al., Signal Transduct Target Ther. 2020; 5:237.

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