August 1, 2020
Evidence, Analytics, Decisions

Ayesha Siddiqua Msc, PhD
Mohit Bhandari MD FRCSC PhD
Editor-in-Chief, OrthoEvidence


  • The scientific community and vaccine industry have come together to develop a vaccine for COVID-19 at remarkable speed.
  • As of July 24, 2020, there have been 25 and 141 vaccine candidates in clinical evaluation and preclinical evaluation, respectively.
  • A wide range of platforms are used for the vaccine candidates, including DNA, inactivated, live attenuated virus, nonreplicating viral vector, protein subunit, replicating viral vector, RNA, and Virus Like Particles (VLP).
  • Several vaccine candidates are ready for Phase 3 trials, yet it is unlikely that any of them will become available before the end of 2020.
  • Vaccine trials typically take several years to conduct – the difficulty of accomplishing this task in a few months have been echoed across the scientific community.
  • There are a wide range of challenges pertaining to the development, licensing, manufacturing, and dissemination process before a vaccine can become available at the population level.
  • The current approach to distributing a future vaccine in an equitable manner around the world can be described as piecemeal at best – with low- and middle-income countries at great disadvantage of accessing the vaccine at the same time as wealthier nations.

The rush for a cure for COVID-19
Since the outbreak of the COVID-19 pandemic, there has been an enormous global effort to develop vaccines against the coronavirus SARS-CoV-2. Vaccines play a critical role in achieving long-term prevention and control of the virus (2). Most recently, went live – where individuals in the US can register to participate in clinical trials for vaccines as well as monoclonal antibody therapies. Given the magnitude of the current public health crisis, vaccine trials are moving at an unprecedented speed and trying to accomplish what usually takes years in months. As of July 24, 2020, there have been 25 vaccine candidates in clinical evaluation and 141 candidates in preclinical evaluation (3,4). Yet, there are a myriad of challenges that must be overcome before a vaccine can be available for use and disseminated in an equitable manner. A nuanced understanding of the current state of vaccines for COVID-19 can help governments, health care systems, clinicians, and the public plan for the months to come.

Lessons from EBOLA, Zika, SARS Vaccine Development: Too little, Too Late.
The COVID-19 pandemic is not the first time the scientific community and the vaccine industry have sought to develop a vaccine at rapid speed. In recent history, the outbreak of H1N1 influenza, Ebola, Zika, and severe acute respiratory syndrome (SARS) all required similar action. A vaccine for H1N1 influenza was developed relatively quickly because technology for influenza vaccine was already well developed (3). The monovalent H1N1 vaccine became available soon after the pandemic peaked in the Northern Hemisphere as a stand-alone vaccine (3). However, vaccines for Ebola, Zika, and SARS did not have similar success – none of them were developed before the respective outbreaks ended.

Historically, there have been several challenges for taking vaccine candidates to clinical development prior to an outbreak. For example, in the case of Ebola, it was not possible to demonstrate clinical efficacy in the absence of an ongoing outbreak, which was further compounded by the lack of interest from the public health system and vaccine industry to invest in the lengthy and expensive process to develop a vaccine without clear demand (2). Nonetheless, the aftermath of each of the previous pandemics has highlighted the need for novel development-and-manufacturing platforms for vaccines for newly emerging pathogens (3). Given this background, SARS-CoV-2 has arrived at a time of increased scientific understanding and innovation, with a variety of vaccine platforms current being developed.

SARS: 2002-2003 SARS outbreak originated in China and spread to 29 countries. SARS is caused by a coronavirus (SARS-CoV), which was identified in 2003. Case fatality rate is around 15%

ZIKA: 2015-2016 Zika outbreak that originated in Brazil and spread to more than 50 countries was the largest outbreak of this virus since it was first discovered in 1947. Zika is a flavivirus that is
transmitted mainly by mosquitos in the genus Aedes. Case fatality rate is around 8.3%

EBOLA:  2014–2016 outbreak in West Africa was the largest Ebola outbreak since the virus was first discovered in 1976; The virus causing the current outbreak in The Democratic Republic of the
Congo and the 2014–2016 West African outbreak belongs to the Zaire ebolavirus species. Case fatality rate is around 50%

How Do Vaccines Work?
Vaccines work by giving us a small amount of a harmless form of a disease, which triggers our bodies to create antibodies to fight it off. If we encounter the disease again in the future, our body can use those antibodies that prevent us from getting sick – thus achieving immunity. (Source: British Society for Immunology).

Early Promise From Phase II Results: Vaccines for COVID-19
Below is a summary of the major platforms, which are technologies used to develop vaccines, that are currently being used for COVID-19 vaccine candidates (Exhibit 1) (3,4). Many developers from around the world are working to evaluate these vaccine candidates (Appendix). Both the US and the UK have already made agreements with Pfizer Inc and German biotech BioNTech SE to buy 100 and 30 million doses, respectively, if their RNA-based vaccine, which is gearing up for a Phase 3 trial, proves to be effective (1,5). Results of two early phase COVID-19 vaccine trials using a nonreplicating factor have been published – a phase 1/2 trial from the UK with support from AstraZeneca, and a phase 2 trial from China with support from CanSino Biologics (6,7). Both
these trials reported the vaccine achieved significant anti–SARSCoV-2 immune responses. Mild adverse events were reported in both trials, such as fever, fatigue, and injection site pain, but neither trials reported severe adverse events. Results of a phase 1 trial in the US for an RNA-based vaccine developed by Moderna also showed significant immune responses in all participants and no trial limiting safety concerns (8). While these trials show promising results, it will likely take a long time before these vaccines become widely available due to a variety of challenges pertaining to their development, licensing and manufacturing process, and dissemination at the population level.

Clinical trials at pandemic speed
There are many challenges associated with designing, conducting, and completing large and complicated trials very fast. Well-conducted trials are resource intensive – they require funding, trained investigators, research staff, and oversight teams (9). Additionally, it typically takes a year or more to develop trial protocols, recruit collaborators, obtain funding and regulatory approval, and launch the trial (9). The difficulty in accomplishing several years worth of work in a few months has been echoed widely across the scientific community – which questions whether it will indeed be plausible to develop new vaccines in an expedited manner.

As an example, the case of the vaccine developed by Moderna illustrates the many operational challenges of conducting trials during a pandemic. A Phase 3 trial of this vaccine was expected to
begin on July 27, 2020. However, Dr. Carlos del Rio, principal investigator at the Moderna site at Emory University in Atlanta, explained “…those target dates move up and down. They won’t let a site start until they’re absolutely ready. Some could start on July 27, and others on August 8″ (10). Although he plans on recruiting participants soon, as of July 9, 2020, he did not receive approval from Emory’s Institutional Review Board to begin the trial (10). There is also the added challenge of recruiting large numbers of participants within a short period of time, which on its own may be an unpredictable process. Dr. Richard Novak, who will be leading the Moderna trial at the University of Illinois at Chicago, noted “I’ve been doing vaccine trials for 25 years, but this is the largest I’ve ever committed to and I just don’t have enough staff and I don’t have enough space” (10).

Beyond the operational challenges, there are many study design related challenges that are difficult to address during a pandemic. Current vaccine trials include small numbers of participants thus any inferences must be made with caution. Phase 3 trials need to be conducted for current vaccine candidates on larger populations of participants to examine their efficacy and safety. However, ideal Phase 3 trials should be rapid, pragmatic, and large enough to address efficacy in different subgroups of interest (11). This is particularly relevant for older adults as well as those with comorbidities, who are typically excluded from clinical trials (11). Ethnic diversity is also important to capture – COVID-19 may impact some ethnic and racial groups more severely than others (12-15). It is important to note that the vaccine trials with published results presented above have limited ethnic diversity. These considerations highlight the importance of including large and representative samples in Phase 3 trials, which is difficult to achieve when there is pressure to proceed with research as quickly as possible given a global health crisis.

Scaling up considerations
While it is reassuring to see several COVD-19 vaccines currently under development, a strong commercialization infrastructure is needed to successfully introduce new vaccines to the market.  Proceeding to Phase 3 trials requires manufacturing to be scaled up to commercial levels for large volumes of safety and immunogenicity data to become available (3). In addition to the financial
investment, there are added challenges for manufacturing COVID-19 vaccines that use novel platforms, which are not licenced nor have gone through previous large-scale manufacturing (3).
These are pressing concerns for the vaccine candidates that are currently gearing up for Phase 3 trials, as they use nonreplicating vectors or RNAs as platforms – neither of which are currently
licensed. To have necessary evidence on the safety and efficacy of the new vaccines, a lot has to happen within a short period of time, including identifying facilities that can produce large volumes
of product, transferring necessary technologies, and adapting manufacturing processes (3). All these steps may be too ambitious to achieve before the end of 2020 – especially when considering the history of developing vaccines for recent pandemics, where most of the required vaccines were not developed until long after the outbreak was over.

Access to Vaccines: Who Gets Them First?
One of the most unfortunate consequences of every pandemic is the exacerbation of existing inequalities. During a time of any global crisis, marginalized populations around the world are
disproportionately disadvantaged along multiple dimensions, including health, education, and finances. Without equitable access to COVID-19 vaccines, the global disparities between high income and low-and middle-income countries (LMICs) can grow even further. The pandemic has already exposed many challenges that can hinder global governance for vaccines. Not only are there significant gaps in the health care systems in many countries, but the current global governance system is fragmented and does not have the necessary structures to pool and share resources to tackle the pandemic (16).  Furthermore, the early days of the pandemic have revealed some concerning trends that question the likelihood of global strategies to preserve health for all – regardless of their country of residence. Medical protectionism has been already observed in many countries when they scrambled to stockpile personal protective equipment and ventilators for their own citizens (16). This mentality could be translated to accessing vaccines when they finally become available – with a real possibility of countries competing against each other for a vaccine bidding war (16).

Ensuring equitable distribution of future vaccines is now a priority for several leading organizations, including Gavi, the Vaccine Alliance. They recently launched the Gavi Covax Advance Market
Commitment (AMC) to subsidise doses for lower-income countries (17). The AMC hopes to raise $2 billion dollars to manufacture the first 20 million doses – however, a much bigger budget is required to provide vaccines for all developing countries (17). There are several other initiatives being floated to ensure equitable access to vaccines for all – however, their approach can be described as piecemeal at best. In June 2020, France, Germany, Italy, and the Netherlands formed the Inclusive Vaccine Alliance (IVA) with the goal of making vaccines affordable and accessible to European Union member states (16). The IVA plans to make a portion of the vaccines available to low income countries – yet, it is not clear how big this portion will be or which countries will receive this support (16). There is a second AMC proposal from Harvard University which presents an “America first” model – where investment would be made in manufacturing capacity to vaccinate all Americans first, and the infrastructure created to protect Americans would be offered to the rest of the world after (17). Beyond the lack of equality and transparency engrained in these proposals for low income countries, middle income countries are largely left out from any vaccine access plans. This is hugely concerning as India and Brazil, both middle income countries, show the highest numbers of daily and overall confirmed cases of COVID-19, following the US (Source: Johns Hopkins University).

Even if governments around the world commit to a fair allocation of vaccine agreement, equitable access to vaccines can still be a challenge if their price is high. For example, for Gavi’s previous AMC fund for pneumococcal vaccines, pharmaceutical companies have demanded a high price (17). Without global engagement with pharmaceutical companies which calls for open discussion regarding the cost of producing the vaccines and adjusting prices accordingly, the real affordability of a vaccine when it becomes available remains uncertain. If high income countries rush to get access to vaccines as soon as possible without negotiating on a fair price, many of the LMICs can be left without vaccines for an exceedingly long time.

We Won’t See A Vaccine in 2020: It’s A Waiting Game
Even amid one of the greatest public health crises we have experienced in recent history, the progress made by the scientific community and vaccine industry to battle COVID-19 has been remarkable. Developing and commercializing any vaccine is a complex process, and even more so during a virus outbreak that requires urgent action. When there is a pandemic, there are high levels of uncertainty and unpredictability across many dimensions, including unpredictable nature of the virus, unpredictable stakeholders and customers, unpredictable timing of need, as well as
unpredictable geographies with increased need (2). While current efforts to introduce a COVID-19 vaccine to the public before the end of 2020 is commendable, it is unlikely to become a reality. In
the meantime, the best course of action is to remain vigilant and engage in preventive practices that minimize the risk of infection, including social distancing, sanitizing, and wearing masks.
Governments, health care systems, and clinicians can continue to enforce and promote these practices in their local settings to curb the pandemic in the foreseeable future.

OE Community Perspectives on COVID-19 Vaccines
We conduced a poll within the OE community to gain their perspectives on COVID-19 vaccines.  Overall, 74% of participants voted that vaccines should be given first to those at highest risk.  In terms of the time when a vaccine would be available, 71% of participants indicted that they feel a vaccine will be ready sometime in 2021 (Exhibit 2). For vaccine distribution around the world, 47%
of participants indicated that developed and developing nations should get access at the same time, even if it means that not everybody in every country will have a full supply.

1.Channel News Asia (2020, July 23). US to pay Pfizer, BioNTech US$1.95 billion for COVID-19 vaccine. Retrieved from:–biontech-us-1-95-billion-for-covid-19-vaccine-12953982
2. Wolf J, Bruno S, Eichberg M, Jannat R, Rudo S, VanRheenen S, & Coller B (2020). Applying lessons from the Ebola vaccine experience for SARSCoV-2 and other epidemic pathogens. NPJ Vaccines; 5(51). DOI: 10.1038/s41541-020-0204-7
3. Lurie N, Saville M, Hatchett R, & Halton J (2020). Developing Covid-19 vaccines at pandemic speed. The New England Journal of Medicine;
382(21): 1969-1973. DOI: 10.1056/NEJMp2005630
4. World Health Organization (2020, July 24). Draft landscape of COVID-19 candidate vaccines. Retrieved from:
5. Pfizer (2020, July 20). Pfizer and BioNTech announce agreement with the United Kingdom for 30 million doses of mRNA-based vaccine candidate
against SARS-CoV-2. Retrieved from:
6. Folegatti PM, Ewer KJ, Aley PK, Angus B, Becker S, Belij-Rammerstorfer S et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine
against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. The Lancet. Published Online First. 20 July 2020.
DOI: 10.1016/S0140-6736(20)31604-4
7. Zhu F, Guan X, Li Y, Huang J, Jiang T, Hou L et al (2020). Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19
vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial. The Lancet. Published Online First.
20 July 2020. DOI: 10.1016/S0140-6736(20)31605-6
8.Jackson LA, Anderson EJ, Rouphael NG, Roberts PC, Makhene M, Coler RN et al. An mRNA Vaccine against SARS-CoV-2 — Preliminary Report.
The New England Journal of Medicine. Published Online First. 14 July 2020. DOI:
9. North CM, Dougan ML, & Sacks CA. Improving clinical trial enrollment – In the Covid-19 era and beyond. The New England Journal of Medicine.
Published Online First. 15 July 2020. DOI: 10.1056/NEJMp2019989
10. Cohen E (2020, July 9). Here’s how to volunteer for a Covid-19 vaccine trial. CNN Health. Retrieved from
11. Bar-Zeev N & Moss WJ. Encouraging results from phase 1/2 COVID-19 vaccine trials. The Lancet. Published Online First. 20 July 2020. DOI:
12.Williamson EJ, Walker AJ, Bhaskaran K, Bacon S, Bates C, Morton CE et al. OpenSAFELY: factors associated with COVID-19 death in 17 million
patients. Nature. Published Online First. 8 July 2020. DOI: 10.1038/s41586-020-2521-4
13. Price-Haywood EG, Burton J, Fort D, & Seoane L (2020). Hospitalization and Mortality among Black Patients and White Patients with Covid-19. The
New England Journal of Medicine; 382(26): 2534-2543. DOI: 10.1056/NEJMsa2011686
14. Trulove S, Abrahim O, Altare C, Lauer SA, Grantz KH, Azman AS, & Spiegel P. (2020). The potential impact of COVID-19 in refugee camps in
Bangladesh and beyond: A modeling study. PLoS Medicine; 17(6): e1003144. DOI: 10.1371/journal.pmed.1003144
15 . Costantine MM, Landon MB, & Saade GR (2020). Protection by exclusion: Another missed opportunity to include pregnant women in research
during the coronavirus disease 2019 (COVID-19) pandemic. Obstetrics and Gynecology; 136(1): 26-28. DOI: 10.1097/AOG.0000000000003924
16. The Lancet (2020). Global governance for COVID-19 vaccines. The Lancet; 395(10241): 1883. DOI: 10.1016/S0140-6736(20)31405-7
17. Usher AD (2020). COVID-19 vaccines for all? The Lancet; 395(10240): 1822-1823. DOI: 10.1016/S0140-6736(20)31354-4