Producing a vaccine that is effective in the ‘real-world’

With healthcare systems around the world struggling to cope with the burden of hospital and critical care admissions resulting from COVID-19, the ability of vaccines to be effective in reducing hospitalisation in a real-world setting and to protect against severe disease and death is of critical importance.


A vaccine against COVID-19 which can reduce disease severity could have a huge impact on the course of the pandemic.1 By preventing infection and even transmission, these vaccines will better help to control disease and pave the way for an easing of the kinds of non-pharmaceutical restrictions currently in place in many countries and regions, such as social distancing.


Figure 1 – Potential endpoints of an efficacious COVID-19 vaccine. Adapted from Hodgson SH et al. Lancet Infect Dis 2020.1


The World Health Organisation (WHO) has defined the minimum efficacy threshold for acceptance of any COVID-19 vaccine as 50%, which could be determined against disease, severe disease and/or transmission of the virus.2  Published modelling data have demonstrated that vaccine efficacy at 60% could have a significant impact on the course of the pandemic, reducing disease severity and hospitalisation rates; 80% efficacy may be able to bring an end to the pandemic, meaning measures such as social distancing could be completely relaxed.3,4

Developing an effective vaccine

Making sure a vaccine is effective in real world settings, with broad access will allow for wide implementation of vaccination programmes at speed. These factors have the potential to have a real impact on the pandemic. For a vaccine to be effective in a real-world setting you need to consider safety, efficacy, durability of response, ease-of-use within the healthcare setting and uptake.



Safety and efficacy

Safety is paramount in any drug development programme. For vaccines in particular, the standard of testing and monitoring is higher than for most other medicines, as vaccines are administered to healthy people.5

This is not the first time in history that a vaccine is being developed at a faster pace than usual to meet public health demands. Following the Ebola outbreak in Guinea in 2016, a vaccine went from early testing to clinical trials within approximately 10 months, which was unprecedented at that time. When a new outbreak of Ebola emerged in 2018, an adenoviral vector vaccine was administered to approximately 300,000 people, which helped to slow the spread of the disease and save lives.6



Over the past 15 years, pandemic preparedness programmes have identified platforms and technology to allow a rapid response to viral pandemics.7 The wealth of documented experience with several types of vaccines in humans is reassuring. This includes experience with approved vaccines across different platforms, such as the one against hepatitis B – a recombinant viral protein that has been available since 1986.8 Recent clinical trial research using viral‑vectored vaccines in Ebola,9 prostate cancer,10 MERS,11 malaria, tuberculosis, and influenza12 have also consistently demonstrated acceptable safety profiles. This pre-existing work has been leveraged in the development of COVID-19 vaccines and will encourage public confidence in this approach.


Performing studies in different geographical locations supports understanding of safety, but also efficacy, in different demographics and sub-populations. It also helps to ensure that the data available have global relevance and instil public confidence in any vaccination programme.

The work does not stop when vaccines are approved, real world evidence can inform longer-term use and address access for specific sub-populations, such as older people or those with underlying health conditions.

Correlation between immune response and durability

Immunogenicity assesses the type of immune response that a vaccine generates and its magnitude over time, and thus it can be a surrogate measure of protection. The level of immune response needed from any vaccine to prevent COVID-19 has not yet been determined. Typically, the immune response induced by a vaccine would be compared to the immune response found in people who have known immunity to a disease.14  

While it is too soon to gauge the optimal immune response to, or the duration of effect of a COVID-19 vaccine, we can refer to results from a previous clinical trial of a vaccine in development against another coronavirus (responsible for causing Middle East Respiratory Syndrome [MERS]) in which an adenoviral vector platform was used. These results demonstrated that the vaccine-induced immune response was maintained for over a year.11 More information about how vaccines work to prime the immune system and how we can measure the immune response can be found here.

Regulatory frameworks to support an agile approach15,16

Under the special circumstances of a pandemic, regulatory authorities have implemented accelerated conditional marketing authorisation or emergency use approval systems. The WHO has also used an emergency use listing to accelerate the pathway to access for low-income countries that may lack robust regulatory processes.17

While working under accelerated timelines, regulatory agencies across the world have worked to ensure vaccine data submitted for approval meet stringent efficacy and safety standards. To achieve this, many countries across the world implemented rolling reviews to enable flexibility in the assessment of data as they become available. These rolling reviews will continue until sufficient data are available to support submission of a formal application for approval.18

Ensuring broad, equitable supply around the world: The cornerstone of any successful global vaccination programme

WHO collaborators have demonstrated that the global public health value of a vaccine is only maximised by ensuring equitable access.19 To change the course of the pandemic, COVID-19 vaccines need to be available globally and be accessible to all who need them. To achieve this, the scalability of production and manufacturing capacity are essential. More about how AstraZeneca is working with partners to achieve equitable access can be found here.

In addition, to ensure ease of access to vaccines, logistical aspects are crucial. Stability, ease-of-use (i.e., no need for specially trained medical staff) and simplicity of distribution, ideally by using a cold chain that is already in place for other vaccines, should be considered. Manufacturing capacity needs to scale as quickly as possible to enable rapid access to as many countries as possible following approval by the regulators. Furthermore, setting up local and regional supply chains reduces the need for transport and supports the resilience of local vaccine infrastructure.

Preparing for the future

To overcome the COVID-19 pandemic, many different vaccines will be needed both to support long-term immunity and for protection against new variants as they arise. In addition, as vaccination programmes are established across the world, investigating the interchangeability across different vaccine platforms, known as ‘heterologous boosting’, may help to make programmes more flexible and potentially improve immunity. Being able to combine different COVID-19 vaccines may be helpful to improved protection and/or to improve vaccine accessibility. This why it is important to explore different vaccine combinations to allow greater flexibility at the time of administering vaccines. It is also likely that combining vaccines may lead to improved immunity over a longer-period of time. 


References

1. Hodgson SH, Mansatta K, Mallett G, et al. What defines an efficacious COVID-19 vaccine? A review of the challenges assessing the clinical efficacy of vaccines against SARS-CoV-2. Lancet Infect Dis. 2021;21 (2): e26-e35.

2. World Health Organisation. WHO target product profiles for COVID-19 vaccines. Available at: https://www.who.int/publications/m/item/who-target-product-profiles-for-covid-19-vaccines [Last accessed: 25 February 2021]

3. The Lancet COVID-19 Commissioners, Task Force Chairs, and Commission Secretariat. Lancet COVID-19 Commission Statement on the occasion of the 75th session of the UN General Assembly. Lancet 2020; 396: 1102–1124

4. Bartsch SM, O'Shea KJ, Ferguson MC, et al. Vaccine efficacy needed for a COVID-19 coronavirus vaccine to prevent or stop an epidemic as the sole intervention. Am J Prev Med 2020; 59: 493-503

5. Vaccine Knowledge Project. How vaccines are tested, licensed and monitored. Available at: https://vk.ovg.ox.ac.uk/vk/vaccine-development  [Last accessed: 25 February 2021]

6. World Health Organisation. The vaccines success story gives us hope for the future. Available at: https://www.who.int/news-room/feature-stories/detail/the-vaccines-success-story-gives-us-hope-for-the-future [Last accessed: 2 March 2021]

7. Sempowski GD, Saunders KO, Acharya P, et al. Pandemic Preparedness: Developing Vaccines and Therapeutic Antibodies For COVID-19. Cell. 2020 Jun 25;181(7):1458-1463.

8. US Centers for Disease Control and Prevention. Epidemiology and Prevention of Vaccine – Preventable diseases. Available at: https://www.cdc.gov/vaccines/pubs/pinkbook/downloads/hepb.pdf [Last accessed: 2 March 2021]

9. Monath TP, Fast PE, Modjarrad K, et al; Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG). rVSVΔG-ZEBOV-GP (also designated V920) recombinant vesicular stomatitis virus pseudotyped with Ebola Zaire Glycoprotein: Standardized template with key considerations for a risk/benefit assessment. Vaccine X. 2019; 1: 100009.

10. Cappuccini F, Bryant R, Pollock E, et al. Safety and immunogenicity of novel 5T4 viral vectored vaccination regimens in early stage prostate cancer: a phase I clinical trial. J Immunother Cancer. 2020; 8 (1): e000928.

11. Folegatti PM, Bittaye M, Flaxman A, et al. Safety and immunogenicity of a candidate Middle East respiratory syndrome coronavirus viral-vectored vaccine: a dose-escalation, open-label, non-randomised, uncontrolled, phase 1 trial. Lancet Infect Dis. 2020;20 (7): 816-826. doi: 10.1016/S1473-3099(20)30160-2. Epub 2020 Apr 21. Erratum in: Lancet Infect Dis. 2020 May 12; Erratum in: Lancet Infect Dis. 2020 Jun 8; PMID: 32325038; PMCID: PMC7172901.

12. Ewer KJ, Lambe T, Rollier CS, et al. Viral vectors as vaccine platforms: from immunogenicity to impact. Curr Opin Immunol. 2016; 41: 47-54.

13. Blonde L, Khunti K, Harris SB, et al. Interpretation and Impact of Real-World Clinical Data for the Practicing Clinician. Adv Ther. 2018; 35 (11): 1763-1774.

14. World Health Organisation. Guidelines on clinical evaluation of vaccines: regulatory expectations. Available at: https://www.who.int/biologicals/BS2287_Clinical_guidelines_final_LINE_NOs_20_July_2016.pdf [Last accessed: 2 March 2021]

15. US Food and Drug Administration. Coronavirus Treatment Acceleration Program (CTAP). Available at: https://www.fda.gov/drugs/coronavirus-covid-19-drugs/coronavirus-treatment-acceleration-program-ctap [Last accessed: 2 March 2021]

16. European Medicines Agency. EMA’s governance during COVID-19 pandemic. Available at: https://www.ema.europa.eu/en/human-regulatory/overview/public-health-threats/coronavirus-disease-covid-19/emas-governance-during-covid-19-pandemic [Last accessed: 2 March 2021]

17. World Health Organisation. Emergency use listing of vaccines. Available at: https://www.who.int/medicines/regulation/prequalification/prequal-vaccines/EUL_PQ_Vaccines/en/ [Last accessed: 2 March 2021]

18. European Medicines Agency. EMA starts first rolling review of COVID-19 vaccine in the EU. Available at: https://www.ema.europa.eu/en/news/ema-starts-first-rolling-review-covid-19-vaccine-eu Last accessed: 2 March 2021]

19. Hogan AB, Winskill P, Watson OJ, et al. Report 33: Modelling the allocation and impact of a COVID-19 vaccine. Imperial College London. Available at: https://www.imperial.ac.uk/media/imperial-college/medicine/mrc-gida/2020-09-25-COVID19-Report-33.pdf [Last accessed: 25 February 2021]


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Veeva ID: Z4-37099
Date of Preparation: October 2021