Platform-Specific Risk Assessment of SARS-CoV-2 Vaccines Using FMEA

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BioPharm International, BioPharm International-02-01-2021, Volume 34, Issue 2
Pages: 15–20

Amid the rush for a SARS-CoV-2 vaccine to deal with the COVID-19 pandemic, a robust risk assessment must be conducted, and mitigation strategies applied.

Vaccines for the prevention of infection with the SARS-CoV-2 virus are being given emergency use authorization by regulatory agencies across the world, based on 70–95% protection against infection and favorable benefit-to-risk profiles. Unprecedented resources have been poured into the development of these vaccines, and the process to develop a safe and effective vaccine needs to be assured. The lack of complete understanding of the immunopathogenesis of COVID-19 SARS-CoV-2, with reports—such as lack of persistence of neutralizing antibodies, aberrant T cell activation, and the quality and quantity of the cytokine storm—makes it difficult to define the precise target profile for inducing sterilizing immunity. The current vaccines have induced protection against infection 7–14 days after vaccination. Limited analysis indicated the subjects develop spike-specific neutralizing antibodies and T cell responses.

Following large-scale manufacturing, the distribution of these novel vaccines will be a long and complex process, and the supply chain and distribution of these vaccines need to ensure that each dose is equivalent, safe, and effective. To systematically analyze the risks of each of the major steps of the vaccine development, the authors of this paper propose performing risk analysis using failure mode and effects analysis (FMEA) on the major platforms of vaccines that are leading in development. This article summarizes the major vaccine platforms and focuses on the process of risk assessment and mitigation strategies that should be applied during the development of these SARS-CoV-2 vaccines needed to prevent development of COVID-19 disease.

Over the recent months, the world has been consumed with the COVID-19 pandemic (1). The need for a safe and effective vaccine that prevents spread and mortality associated with the disease is extremely urgent and has led to the granting of emergency use authorizations worldwide (2,3).

The diversity of clinical symptoms due to the viral infection continue to evolve (4,5). The disease ranges from asymptomatic conditions to mild, moderate, severe, and critical conditions. The goal of all the vaccines is to prevent infection and curb progression to severe disease. The platforms on which vaccines are being developed against SARS-CoV-2 include protein vaccines, nucleic acids vaccines, viral-vectors vaccines, inactivated virus vaccines, and live attenuated vaccines (6,7). The rush for a vaccine, however, will have unforeseen impacts on the population and rare adverse effects, which will not be observed until after the vaccine has been administered to a large number of people. Hence, robust risk assessment of the vaccines must be conducted.

Risk assessment process

The process of risk assessment is carried out by analyzing, identifying, and evaluating risks involved in the entire process of drug development, including the discovery, manufacturing, distribution, and inspection, as described in the International Council for Harmonization Q9 (ICH Q9) guidance (8). This FMEA risk management approach defines the risks by accessing severity, occurrence, and detectability (9) (Figure 1). The process comprises the following steps, which ask the following specific questions:

  • Function/unit operation: a step used to define the process step (stage) undergoing the analysis; “What attribute is the risk being evaluated for?”
  • Failure mode: ways by which the described function can fail to meet the purpose or give unintended results; “What can go wrong?”
  • Effects: failure mode leads to various effects where it impacts a particular step in the process going wrong. These effects are ranked by severity scores; “What is the impact of the failure?
  • Causes: this step helps to define the reasons why failure prevails;“What is the cause of the failure?”
  • Actions: resolving these causes by taking relevant actions thus help in mitigating the risks in the process; “What can be done to mitigate the failure?”

The obtained ranks of severity (S), occurrence (O), and detectability (D) are used to calculate the risk priority number (RPN) = S*O*D. These actions are prioritized to develop a systematic risk mitigation strategy. An example of function, requirement, and failure mode is depicted in Figure 2.

Risk mitigation

After identifying, listing, prioritizing, and ranking the risks for each vaccine, the risk mitigation strategy requires each risk to have a mitigation action. The list below provides an example of criteria (requirements) for a successful vaccine and potential adverse events (failure modes) that could occur.

Requirements of a vaccine

Several elegant articles have articulated the design, platforms, and challenges in developing vaccines for prevention of infection with SARS-CoV-2 (6,7,10,11). To describe the process of assessing risks associated with a vaccine, a list of the criteria that a successful vaccine should achieve follows.

Criteria for a successful vaccine

The vaccine should induce a sustained protective humoral response (e.g., a neutralizing antibody titer for >1:2560 for >1 year) and a cell-mediated T-cell response (e.g., a four-fold increase in interferon (IFN)-secreting enzyme-linked immunosorbent spot [ELISPOT] response by CD4+ and CD8+ T cells):

  • The vaccine should induce a sustained memory immune response (e.g., presence of spike-antigen-specific memory CD4+ and CD8+ T cells) and memory B cells.
  • The vaccine should confer protection on a large number of individuals, that can enable herd immunity (e.g., >70% of the immunized subject).
  • The vaccine should elicit protective immune responses in all groups of individuals (e.g., infants 0–2 years, young children 2–18 years, adults 18–60 years, pregnant women, older adults > 60 years, and individuals with comorbid conditions, such as diabetes, heart disease).
  • The vaccine should be safe and not result in anaphylactic shock (e.g., in < 0.1% of the immunized individuals) or severe allergic or systemic inflammatory immune responses.
  • The vaccine should be stable (e.g., the formulation should enable stability during shipment, storage, and distribution at room temperature for at least three months).
  • The vaccine should provide mucosal immunity (e.g., prevent infection through the respiratory tract).

Defining these requirement criteria is the first step of the FMEA risk assessment process. To anticipate the potential harmful effects of the vaccine, the potential points of failure associated with safety adverse events have been listed.

Major adverse events

Based on experiences with previous vaccines (3,6,12–16), the list below is an example of the potential adverse-events that could occur:

  • The vaccine could elicit an anaphylactic shock due to an allergic response to either the vaccine antigens or formulation components (e.g., in >0.1% of the immunized individuals).
  • The vaccine could induce cross-reactive antibodies to self-proteins and cause autoimmune conditions (e.g., in > 0.1% of the immunized individuals).
  • The vaccine can induce severe local injection site reactions (e.g., > 5% of the immunized individuals).
  • The vaccine could cause induction of antibody dependent enhancement of SARS-CoV-2 (17) through interaction with Fc receptors (e.g., in > 0.1% of the immunized individuals).
  • The activation of the antigen-specific immune responses may create a reservoir of highly infectable cells in vaccinated individuals, previously observed in an HIV vaccine (18).
  • The vaccine could result in a weak immune response and not provide adequate levels of herd immunity, enabling spread of the virus in the community (e.g., > 10% subjects with a titer <1:20).
  • The vaccine could exacerbate comorbidities, such as diabetes, heart disease, etc. (e.g., in > 10% of such patients).

The list of criteria and potential adverse events listed here are starting points for a more detailed list that would need to be developed for each of the vaccines. A more thorough review requires cross-functional teams to perform the assessment for each individual vaccine in development, and the steps of the FMEA process should be a collective effort by cross-functional teams. The FMEA process ensures all risks are listed, scored, and prioritized, and that risk-mitigation action lists are developed.

Platform classes and potential risks

Nucleic acid vaccines

One of the rationales for the use of messenger RNA (mRNA) and DNA vaccines has been to avoid viral-vector mediated inflammatory immune responses. The mRNA vaccines that have been developed—mRNA-1273 (Moderna) (19,20) and BNT162b2 (Pfizer-BioNTech) (21,22)—encode the SARS-CoV-2 spike protein (23). An FDA advisory committee have conducted a detailed review of these two mRNA vaccines (24,25). Meanwhile, a DNA vaccine (INO-4800, Inovio) that expresses the SARS-CoV-2 spike protein is also in development (26). The safety adverse events associated with mRNA and DNA vaccines include degradation of the mRNA and DNA, resulting in the lack of effective expression of the antigen for prolonged stimulation of the immune system, and local injection site reactions. In addition, there is a potential risk of genetic integration through potential endogenouse reverse transcptases, and jumping genes (retrotransposons) (27).

Viral Vectors

The use of viral vectors as vehicles for inducing immune responses against pathogens has been tested for several viruses (11,14,28,29). The severe adverse events induced by adenovirus in the clinical trial for ornithine transcarboxylase underscores the potential safety concerns of these vectors (30). Several viral vector vaccines are in the pipeline. ChAdOx1 nCoV-19 (Oxford, AstraZeneca), which expresses the SARS-CoV-2 spike protein, consists of chimpanzee–adenovirus vector (31–33). The Phase III trials for this vaccine candidate have compared its efficacy and safety to the control meningococcal conjugate vaccine (MenACWY) (34). The adenovirus serotype 26 (Ad26) vector (also expressing the virus spike protein) vaccine (Janssen) is being developed in Phase I and II trials, and initial trials suggest that a single dose of this vaccine may induce sufficient protective immune responses (35). Another adenovirus-based vaccine expressing spike protein, adenovirus serotype 5 (Ad5) vector vaccine (CanSino Biologics), completed clinical trials in Wuhan, China, in healthy adults (36). Meanwhile, the Sputnik V vaccine (Gamaleya National Center of Epidemiology), which contains both Ad5 and Ad26 adenovirus vectors, expresses the gene for the SARS-CoV-2 spike glycoprotein in separate adenoviral vectors of serotypes (37).

Major risks associated with protein vaccines include adverse events related to viral vectors in the presence of pre-existing antibodies, which can prevent efficient antigen uptake and presentation. Primary immunization, which results in antibody generation to the vector, can attenuate the response to booster doses. Using heterologous vectors for prime and boost doses can overcome these challenges, however. In addition, the presence of pre-existing immune responses to the vector can have different safety adverse events than subjects that do not have these responses.

Protein vaccines

Protein subunit vaccines have been utilized effectively against pathogens (38). These vaccines are effective in activation of humoral immune responses; it remains to be seen if they can elicit activation of cytolytic T-cell responses. The NVXCoV2373 vaccine (Novavax) consists of a recombinant protein expressed from the genetic sequence of the SARS-CoV2 spike protein (39). It utilizes nano-particle-based technology using the coronavirus spike (S) protein and contains saponin-based Matrix-M adjuvant (AGC Biologics, Seattle). Clinical trials for NVXCoV2373 are in progress (40).

The anticipated risks of the protein vaccines include a limited ability to induce CD8 cytotoxic T-cell responses. It is possible that the use of the novel nano-particle technology and use of the Matrix-M adjuvant may induce sufficient activation of the CD8 response.

Inactivated whole virus

PiCoVacc(Sinovac Biotech, China) and Covaxin (Bharat Biotech, India) are purified inactivated SARS-CoV-2 virus vaccine candidates. According to clinical study results, the medium dose was selected to enter into Phase III trial (11).

The major risks associated with inactivated whole virus vaccines stems from the fact that inactivation of viruses for vaccines can potentially and inadvertently contain live virus in the preparation. There can be more adverse inflammatory responses induced by such vaccines.

Live attenuated vaccine

Codagenix, a US-based clinical-stage synthetic biology company, is developing live attenuated viral vaccine using a codon deoptimization process, which weakens virus antigenicity. This process generates highly attenuated viruses that are stable and have a barrier to wildtype reversion, while retaining 100% amino-acid-sequence identity to the parent virus.Other approaches of developing these vaccines include growing the virus in unfavorable conditions, such as low temperature or growing them in non-human cells. Live attenuated vaccine can activate both humoral and cellular immune response necessary for viral clearance from upper respiratory tract.

The disadvantages and risks associated with live attenuated vaccines include safety concerns and a time-consuming process of conventional development. Similar to inactivated whole virus vaccines, live attenuated viruses for vaccines also have the potential to inadvertently contain live virus in the preparation, which can lead to more adverse inflammatory responses.

Supply chain/distribution

Among the supply-chain challenges that SARS-CoV-2 vaccine makers face is the reality that billions of doses will need to be manufactured and distributed all over the world. The goals for creating such a network is described by the six rights of supply-chain management as defined by the World Health Organization (41):

  • Right product—how does the network ensure that the right vaccine product reaches every patient? Looking at the scale of the COVID-19 pandemic, demand will outstrip the supply, and counterfeiting is likely to emerge as a major risk. Appropriate measures for authenticating the vaccine product would be required.
  • Right quantity—it is important that the vaccine product reaches the patient in the required quantity. Unlike other resources, vaccines are likely to be ineffective and possibly dangerous if not given in the right quantity.
  • Right condition—Vaccines being heat labile products, temperature requires to be rigorously controlled in the cold chain (42) from manufacturer to wholesaler, retailer, and patient. The cold chain gets even more complicated in emerging and underdeveloped economies. The vaccine can not only become ineffective but could become unsafe for patients if not served in right condition.
  • Right place—for a vaccine product to reach the patient, it needs to reach the caregiver to be administered to the patients. Shipments needs to be monitored to ensure their safe delivery to the target.
  • Right time—with everyone scrambling to get access to a safe and effective vaccine, and with the contagious nature of the pandemic, it will be a challenge and a requirement to get the vaccine in a timely manner.
  • Right cost—For the vaccine to reach every patient worldwide, cost will clearly play a major role. The world’s richest nations have already locked in the required supply of SARS-CoV-2 vaccines with the major manufacturers.


The need for vaccines against SARS-CoV-2 is one of the most important defenses against the COVID-19 pandemic. With at least seven different vaccine platforms at work and more than 100 vaccines in development (11), and with an uncertain understanding of the immuno-pathogenesis of the disease (43,44), risk assessment is a daunting task. The authors of this paper have utilized a systematic FMEA approach to evaluate and prioritize the risks associated with each vaccine platform.

The SARS-CoV-2 vaccine risk assessment requires a thorough understanding of the mechanism of action by which each of the vaccines induce activation of the immune responses. Induction of an ineffective effector immune response can also pose risks to herd immunity (45). Each platform has a different risk/benefit profile. It remains to be seen which of the vaccine platforms elicit long-term protective immune responses with minimal adverse events. As shown, a summary of the risk analysis conducted across the different platforms has been shown in Table I to provide a comparative analysis. While the authors performed a FMEA on the major risks, it is critical for the in-house teams developing these vaccines to perform a much more in-depth analysis to ensure optimal safety and efficacy for patients.

Requirements for supply chain and distribution of the vaccine can be categorized into quantity, condition, place, time, and cost. Each of these categories is associated with risks that need to be systematically evaluated by the manufacturer, supplier, distributor, and the end-user.

In summary, it is strongly recommended that a detailed risk analysis be performed for each of the SARS-CoV-2 vaccines in development by a collaborative effort from cross-functional teams. It is also recommended that the FMEA approach be used with accompanying software to handle the multi-dimensional nature of the risk assessment process. Ensuring that the vaccines are safe and effective will help mitigate the potential for additional calamities, which can otherwise be anticipated.


1. A.S. Fauci, H.A.O. Lane, and R.R Redfield, N Engl J Med 382, 1268–1269 (2020).
2. D. Cryanoski and S. Mallapaty, Nature 585, 331–332 (2020).
3. A. Allen and L. Szabo, “NIH ‘Very Concerned’ About Serious Side Effect in Coronavirus Vaccine Trial,”, Sept. 24, 2020.
4. D. Blanco-Melo, et al., Cell 181, 1036–1045 (2020).
5. N. Vabret, et al., Immunity 52 (6) 910–941 (2020).
6. E. Callaway, Nature 580, 576–577 (2020).
7. P.M. Heaton, N Engl J Med. 383, 1986–1988 (2020).
8. ICH Q9 Quality Risk Management, Step 4 (2005).
9. N. Chirmule, et al., J Pharm Sci 109, 3214–3222 (2020).
10. F. Amanat, and F. Krammer, Immunity 52, 583–589 (2020).
11. F. Krammer, Nature 586, 516–527 (2020).
12. WHO, “Dengue Vaccines,”, April 20, 2018.
13. M. Amaya and C.C. Broder, Annu Rev Virol 7, 447–473 (2020).
14. V. Bernasconi, et al., Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 63, 65–73 (2020).
15. S. Gao, S. Song, and L. Zhang, Front Microbiol 10, 2881 (2019).
16. E. Prompetchara, et al., Asian Pac J Allergy Immunol 38, 178–185 (2020).
17. A. Iwasaki and Y. Yang, Nat Rev Immunol 20, 339–341 (2020).
18. G. Gray, S. Buchbinder, and A. Duerr, Curr Opin HIV AIDS 5, 357–361 (2010).
19. L.A. Jackson, et al., N Engl J Med. 383, 1920–1931 (2020).
20. E. Callaway, Nature 587, 337–338 (2020).
21. E.E. Walsh, et al., N Engl J Med. 383, 2439–2450 (2020).
22. F.P. Polack, et al., N Engl J Med. 383 (27) 2603–2615 (2020).
23. M.J. Mulligan, et al., Nature 586 (7830) 589–593 (2020).
24. FDA, “FDA Briefing Document Moderna COVID-19 Vaccine,”, Dec. 17, 2020.
25. FDA, “FDA Briefing Document Pfizer-BioNTech COVID-19 Vaccine,”, Dec. 10, 2020.
26. R.F. Smith, et al., Nat Commun 11, 2601 (2020).
27. L. Zhang, et al., “SARS-CoV-2 RNA Reverse-transcribed and Integrated into the Human Genome,”, Dec. 13, 2020.
28. M. Fragoso-Saavedra and M.A. Vega-López, J Leukoc Biol. 108 (3) 835–850 (2020).
29. C.E. Mire, et al., Emerg Infect Dis 25, 1144–1152 (2019).
30. S.E. Raper, et al., Mol Genet Metab 80, 148–158 (2003).
31. M.D. Tapia, et al., Lancet Infect Dis 20, 719–730 (2020).
32. N. van Doremalen, et al., “ChAdOx1 nCoV-19 Vaccine Prevents SARS-CoV-2 Pneumonia in Rhesus Macaques,”, May 13, 2020.
33. A.O. Hassan, et al., Cell 183 (1) 169–184 (2020).
34. M. Voysey, et al., Lancet 397, 99–111 (2021).
35. L.H. Tostanoski, et al., Nat Med 26, 1694–1700 (2020).
36. F.C. Zhu, et al., Lancet 395, 1845–1854 (2020).
37. Y. Logunov, et al., Lancet 396, 887–897 (2020).
38. P. Piot, et al., Nature 575, 119–129 (2019).
39. M. Guebre-Xabier, et al., Vaccine 38, 7892–7896 (2020).
40. C. Keech, et al., N Engl J Med. 383, 2320–2332 (2020).
41. WHO, “Immunization Supply Chain and Logistics,”, accessed Oct. 30.2020.
42. M. Zaffran, et al., Vaccine 31 (Suppl 2), B73-B80 (2013).
43. L. Kuri-Cervantes, et al., “Immunologic Perturbations in Severe COVID-19/SARS-Cov-2 Infection,”, May 18, 2020.
44. L. Kuri-Cervantes, et al., Sci Immunol 5 (49) eabd7114 (2020).
45. E. Randolph and L.B. Barreiro, Immunity 52, 737–741 (2020).

About the authors

Rajika Jindani is a medical resident at University of Miami. Smritie Sheth is scientific manager, and Narendra Chirmule*,, is CEO; both are at SymphonyTech Biologics. Soumya Paul is CEO at Pentavalent Biosciences. Anurag Rathore is a professor in the Department of Chemical Engineering at the Indian Institute of Technology New Delhi and a member of BioPharm International’s Editorial Advisory Board.

*To whom all correspondence should be addressed.

Article Details

BioPharm International
Vol. 34, No. 2
February 2021
Pages: 15–20


When referring to this article, please cite it as J.R. Jindani, et al., “Platform-Specific Risk Assessment of SARS-CoV-2 Vaccines Using FMEA,” BioPharm International 34 (2) 2021.