COVID-19 Vaccines: Critical New Tools in the Fight Against the Global Pandemic

As several different COVID-19 vaccines are authorized for emergency use and/or approved around the world, the race to contain the pandemic has been given a new weapon. This chapter explores the COVID-19 vaccine landscape — based on data available as of May 31, 2021 — the various strategies for vaccine rollout, and the opportunities and challenges concerning equitable vaccine access.

With COVID-19 being a highly infectious disease, vaccine development is key to protecting the global populations against SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) and preventing its viral transmission. Generally, it takes a vaccine up to 10 years to go from laboratory and clinical testing to receiving country regulatory approval (see Figure 1).1,2

FIGURE 1  |  COVID-19 vaccine development compared to traditional vaccine development 

For the COVID-19 vaccines, there are several factors that allowed these timelines to be accelerated without skipping any steps in the development process while ensuring their safety and efficacy. Unprecedented funding from private and public sources allowed vaccine developers to run multiple clinical trials at the same time and manufacture product prior to country regulatory approval. For some vaccines, researchers used existing national or global clinical trial networks to rapidly recruit participants and conduct the trials. Even though some vaccine technologies may appear new, they actually leverage decades of research and experience against various infectious diseases (e.g., influenza, severe acute respiratory syndrome or SARS). Finally, vaccine developers closely collaborated with country regulators who expedited the pathway for vaccine authorization and/or approval. By the end of 2020, within one year of the initial outbreak, the world had multiple vaccines available for use. 

Vaccines train the immune system to build a response by producing antibodies to protect people from contracting or developing severe COVID-19 disease and transmitting it to others. These are critical steps to controlling the spread of the virus.3,4

Of the COVID-19 vaccines authorized (as of April 30, 2021), four main vaccine platforms or technologies are utilized (see Figure 2 for a detailed overview). 

FIGURE 2  |  COVID-19 vaccine platforms (as of April 30, 2021)

mRNA vaccines contain synthetic strands of genetic material called mRNA that provide instructions for immune cells to produce harmless spike proteins, which are also found on the surface of SARS-CoV-2.5,6 Once the spike proteins are produced, immune cells break down and remove the mRNA, preventing it from entering the nucleus of the cell. Thus, mRNA vaccines cannot alter DNA. Immune cells display the vaccine-generated spike proteins on their surface to generate an immune response and make antibodies similar to what happens during a COVID-19 infection. Although mRNA vaccines are now being used for the first time in humans for COVID-19, the technology has been studied for over 20 years against various diseases (e.g., influenza, rabies). 

Viral vector vaccines developed for COVID-19 use a modified version of adenoviruses as vectors.7,8 Adenoviruses are common viruses that infect humans, causing mild respiratory and gastrointestinal tract infections. When adenoviruses are used as a vaccine vector, they are modified to be unable to reproduce and cause infection. Once inside the cell, the adenovirus vector delivers instructions to make harmless spike proteins. Since the adenovirus vector vaccines do not contain the live virus, recipients cannot get COVID-19 disease from the vaccine. Prior to using the adenovirus vector vaccines for COVID-19, the platform was used in Europe for an Ebola vaccine. 

Protein subunit vaccines use specific parts of the virus, spike proteins or peptides, to stimulate the immune system. Protein subunit vaccines do not contain the entire virus pathogen.9,10 Protein subunit vaccines have been successfully used to protect people from various diseases (e.g., hepatitis B, pertussis).

Inactivated virus vaccines use the entire virus, which has been killed or modified using chemicals, heat, or radiation to make it unable to replicate and cause infection.11,12 Most non-COVID-19 vaccines available today use this platform (e.g., influenza, polio) since it can induce strong antibody response. However, these vaccines require special laboratory facilities to safely grow the virus, have a relatively long production time, and require booster shots for ongoing protection — not ideal in a global pandemic where time is of the essence. 

THE RACE TO VACCINATE 

Each country has developed its own strategy for protecting its population, influenced by the vaccine platform authorized, supply, and the regional epidemiology of the pandemic (e.g., number of and change in new cases, severity of disease, circulating variants).

As shown in Figure 2, the majority of authorized or approved vaccines require a two-dose schedule.13,14 For countries that follow the manufacturers’ guidelines or clinical trial evidence, this strategy is ideal if vaccine supply is relatively adequate. However, the vaccine rollout may slow down as the countries need to reserve supply for the second dose.

The United Kingdom and Canada have implemented a strategy to delay the second dose, contrary to the manufacturers’ guidelines, in order to protect the largest number of individuals in the population as early as possible with a single dose while optimizing limited supply.15,16 An exploratory analysis of the Oxford-AstraZeneca vaccine showed vaccine efficacy (VE) against symptomatic COVID-19 after one dose was 76 percent during the first 90 days.17 Additionally, VE after the second dose was higher (81 percent) with a dosing interval of 12 weeks or more compared to a dosing interval of less than six weeks (55 percent). This is not the first vaccine to demonstrate greater protective efficacy with wider dosing interval — influenza, Ebola, and malaria vaccines have also demonstrated similar effects. 

Although there are clear advantages with this strategy, there are some uncertainties. It is unclear if partial vaccination would increase the risk of viral mutations, which may lead to the emergence of new variants. As for the recipients, there are concerns some may forget to return for their second dose, have confusion with vaccination schedule, and/or believe one dose provides adequate protection.18 

For the vulnerable, at-risk populations (e.g., people who are older, are immunocompromised, or have end stage kidney disease), the duration of vaccine protection may be different, which raises the question of whether they should be exempt from this strategy and may require an additional (booster) dose to achieve the same level of protection as the general population. 

Most countries have created a vaccine strategy based on age, with priority given to older people who are at higher risk for severe COVID-19 disease and death. Some countries have also prioritized healthcare workers, to ensure they are protected while they help sustain the healthcare system. As vaccine supply increases, some countries have expanded their prioritization lists to include people with chronic medical conditions who are highly vulnerable to COVID-19 (e.g., immunocompromised, ESKD). Emerging evidence has demonstrated that individuals with ESKD do develop and maintain an immune response after an infection or vaccine, and implementation of full vaccination protocols optimizes their protection.19

Recently, some countries have been evaluating or have approved combining different vaccines for the two-dose regimen.20 Mixing vaccine doses may be attractive in countries where there is a supply shortage with the first-dose vaccine; using another vaccine for the second dose would overcome this issue as well as help people get vaccinated faster. Mixing vaccines may also be used when safety issues arise after the first dose that cause the recipients to be unable or unwilling to get a second one (e.g., severe allergic reactions, rare blood clots). Experts are evaluating if mixing two different vaccine platforms (e.g., adenovirus vector with mRNA) could enhance protection. Some uncertainties associated with this strategy include its impact on the efficacy of future booster dosing (if needed) and whether side effects are increased. 

Regardless of what vaccine strategy/strategies a country adopts, the goal is to achieve a high vaccination rate to help people build immunity against COVID-19, a very contagious disease. During the early phase of the global vaccine rollout, there were hopes that once enough people were immunized, herd immunity could be achieved, and viral transmission reduced. Based on experience from past infectious disease control, there are many barriers that can impact vaccine uptake, some of which have been identified in Figure 3.21 Any of these factors, alone or in combination, will make it challenging to eliminate SARS-CoV-2 globally. In fact, is it realistic to expect to eliminate such a contagious virus over a short period? Despite discovering a vaccine for smallpox in 1796, this contagious disease was not globally eradicated until 1980, following almost 30 years of a coordinated WHO global campaign.22

FIGURE 3  |  Potential barriers to vaccination

If COVID-19 cannot be eradicated, then it is likely the virus will become an endemic disease, similar to influenza and four human coronaviruses that cause the common colds.23 Through vaccination, acquired immunity from infection, and non-pharmacological interventions, some regions may be able to eradicate or substantially contain the virus. In other regions, COVID-19 will continue to circulate, but the annual number of infections, impact of the virus (severity and death), and need for social isolation will lessen. With the future of COVID-19 being unknown, it is critical for people to continue to adhere to public health mitigation measures (e.g., vaccinations, maintaining good hand hygiene) to reduce the spread of the virus.

THE IMPORTANCE OF EQUITABLE VACCINE ALLOCATION

The rapid development of COVID-19 vaccines has brought hope of potentially controlling this pandemic. However, this is only possible if everyone around the world has access to the vaccines. Despite the fact that many countries have accelerated the authorization or approval of different vaccines, some of these countries still do not have access to them. The following identifies several potential reasons why inequalities in vaccine allocation exist:24

• Higher income countries have secured the available vaccine supply.
• Manufacturers are unable to provide vaccine supply despite efforts to ramp up production.
• The geographical landscape of a country may challenge vaccine distribution and/or storage requirements. 
• Lower- and medium-income countries are unable to afford the cost of vaccines.
• There is limited access to vaccine intellectual property. 
• There are restrictions or bans on exporting vaccines and/or raw materials needed to produce vaccines.

To help ensure equitable global access to vaccines, tests, and treatments regardless of a country’s wealth, a global initiative named COVAX, co-led by the Coalition for Epidemic Preparedness Innovations (CEPI), Gavi and the World Health Organization (WHO), alongside a key delivery partner UNICEF was created. COVAX helps to develop, manufacture, and distribute vaccines in bulk while ensuring that the ability to pay is not a barrier to access.25

As of July 7, 2021, 51 percent of individuals in high-income countries have received at least one dose, even though they account for 19 percent of the global adult population (Figure 4).27 As for low-income countries, only one percent of their population have received at least one dose, followed by 14 percent in low middle-income countries. Additionally, disparities in vaccines are further impacted by region, with 40 percent of Europe's population having received at least one dose, followed by the Americas (39 percent), while the African region has the lowest rate (2 percent) followed by Eastern Mediterranean region (9 percent). Critical to closing the disparities between countries, vaccine supply needs to be accessible and vaccination rates need to be increased. Therefore, it is imperative that high-income countries lead by example and assist in making vaccines accessible to everyone, which may require they share their existing or excess supply.

FIGURE 4  |  Vaccine doses purchased by income level compared with share of global adult population (as of July 7, 2021)

CONCLUSION

The future of COVID-19 vaccines is promising. In addition to the list of authorized vaccines already identified, over 90 vaccines are in clinical development and over 190 vaccines are in pre-clinical development.28 The ease and success of the global vaccination program will be enhanced if these newer vaccines are available as a single dose, have easy storage and transport requirements, and offer novel forms of delivery (intranasal, subcutaneous, oral, etc.). 

For the world to return to a “new normal” where people can safely socialize and travel again, a planned and phased approach to reopening and continued support of various public health measures (e.g., optimizing vaccinations, non-pharmaceutical interventions) will be critical. As COVID-19 evolves from being a pandemic to endemic disease, it is hoped that the virus will primarily cause mild to moderate disease and be less likely to cause severe disease and deaths in vaccinated individuals, especially in vulnerable populations.

Meet The Experts

References

1. Boston Consulting Group. Lessons learned from the frontline of the global COVID-19 vaccine rollout. March 2021. https://media-publications.bcg.com/BCG-Executive-Perspectives-Vaccine-Rollout.pdf.
2. McKinsey and Company. On pins and needles: tracking COVID-19 vaccines and therapeutics. February 18, 2021.
3. World Health Organization. COVID-19 vaccines. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/covid-19-vaccines. Accessed May 13, 2021.
4. Centers for Disease Control and Prevention (CDC). Understanding how COVID-19 vaccines work. Last updated March 4, 2021. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/different-vaccines/how-they-work.html.
5. Kyriakidis NC, Lopez-Cortes A, Gonzalez EV, et al. SARS-CoV-2 vaccines strategies: a comprehensive review of phase 3 candidates. npj Vaccines 2021;6:28. https://doi. org/10.1038/s41541-021-00292-w.
6. Centers for Disease Control and Prevention. Understanding mRNA COVID-19 vaccines. Last updated March 4, 2021. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/different-vaccines/mrna.html. 
7. Kyriakidis et al. SARS-CoV-2 vaccines strategies.
8. Centers for Disease Control and Prevention. Understanding viral vector COVID-19 vaccines. Last updated April 13, 2021. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/different-vaccines/viralvector.html.
9. CDC. Understanding how COVID-19 vaccines work.
10. Kyriakidis et al. SARS-CoV-2 vaccines strategies.
11. Ibid.
12. Gavi, The Vaccine Alliance. What are whole virus vaccines and how could they be used against COVID-19? https://www.gavi.org/vaccineswork/what-are-whole-virus-vaccines-and-how-could-they-be-used-against-covid-19#:~:text=Whole%20 virus%20vaccines%20use%20a,but%20does%20not%20cause%20illness. Accessed May 14, 2021. 
13. US National Library of Medicine, ClinicalTrials.gov; COVID 19 Vaccine Tracker. https://covid19.trackvaccines.org. Accessed May 14, 2021. 
14. European Medicines Agency. COVID-19 pandemic. ema.europa.eu. Accessed May 14, 2021.
15. UK science advisers: publish evidence behind COVID vaccine dosing strategy. Editorial. Nature 2021;589:169-70. https://doi.org/10.1038/d41586-021-00045-8.
16. National Advisory Committee on Immunization. Extended dose intervals for COVID-19 vaccines to optimize early vaccine rollout and population protection in Canada in the context of limited vaccine supply. Advisory Committee Statement, April 14, 2021. https://www.canada.ca/content/dam/phac-aspc/documents/services/immunization/national-advisory-committee-on-immunization-naci/naci-summary-extended-dose-interval-covid-19-en.pdf.
17. Voysey M, Costa Clemens SA, Madhi SA, et al. Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials. Lancet 2021 Mar 6;397(10277):881-91. doi: 10.1016/S0140-6736(21)00432-3.
18. Kadire SR, Wachter RM, Lurie N. Delayed second dose versus standard regimen for Covid-19 vaccination. N Engl J Med 2021 Mar 4;384(9):e28. doi: 10.1056/NEJMclde2101987.
19. Ikizler TA, Coates PT, Rovin BH, Ronco P. Immune response to SARS-CoV-2 infection and vaccination in patients receiving kidney replacement therapy. Kidney Int 2021 Apr 20:S0085-2538(21)00391-4. doi:10.1016/j.kint.2021.04.007.
20. Callaway E. Mix-and-match COVID vaccines trigger potent immune response. Nature 2021;593(7860):491. https://doi.org/10.1038/d41586-021-01359-3.
21. Zhang Y, Fisk, RJ. Barriers to vaccination for coronavirus disease 2019 (COVID-19) control: experience from the United States. Glob Health J 2021;5(1):51-55. doi:10.1016/j.glohj.2021.02.005.
22. World Health Organization. Smallpox. https://www.who.int/health-topics/smallpox#tab=tab_1. Accessed May 27, 2021.
23. Phillips N. The coronavirus is here to stay—here’s what that means. Nature 2021 Feb;590(7846):382-84. https://doi.org/10.1038/d41586-021-00396-2.
24. Acharya KP, Ghimire TR, Subramanya SH. Access to and equitable distribution of COVID-19 vaccine in low-income countries. npj Vaccines 2021 6:54. https://doi. org/10.1038/s41541-021-00323-6.
25. Berkley S. COVAX explained. Gavi, the Vaccine Alliance. Sept. 3, 2020. https://www.gavi.org/vaccineswork/covax-explained.
26. Rouw A, Wexler A, Kates J, et al. Global COVID-19 vaccine access: a snapshot of inequality. Kaiser Family Foundation Policy Watch. March 17, 2021. https://www. kff.org/policy-watch/global-covid-19-vaccine-access-snapshot-of-inequality/.
27. Rouw A, Wexler A, Kates J, Michaud J. Tracking global COVID-19 vaccine equity. Kaiser Family Foundation, July 21, 2021. https://www.kff.org/coronavirus-covid-19/issue-brief/tracking-global-covid-19-vaccine-equity/.
28. World Health Organization. Draft landscape and tracker of COVID-19 candidate vaccines. May 11, 2021. https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines.