Vaccine-associated enhanced disease: Case definition and guidelines for data collection, analysis, and presentation of immunization safety data

Muñoz, Flor M.; Cramer, Jakob P.; Dekker, Cornelia L.; Dudley, Matthew Z.; Graham, Barney S.; Gurwith, Marc; Law, Barbara; Perlman, Stanley; Polack, Fernando P.; Spergel, Jonathan M.; Braeckel, Eva Van; Ward, Brian J.; Didierlaurent, Arnaud M.; Lambert, Paul Henri

doi:10.1016/j.vaccine.2021.01.055

Cited by 80 publications

(80 citation statements)

References 129 publications

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“…For comparisons among formulations, however, this risk was mitigated, to some extent, by the fact that results across the three CoVLP dose levels were quite consistent (n = 60 for CoVLP alone or with each adjuvant). Other obvious concerns that apply to all early-phase trials of COVID-19 vaccines are the lack of reference reagents or standardized assays to permit comparisons across studies, the absence of well-defined correlates of immunity and no simple definition of VAED 55 . Regarding reagents, assays and correlates, it is reassuring that the adjuvanted CoVLP formulations elicited NAb responses that were at least as high as those seen in convalescent serum/plasma, including the characteristically higher responses seen in hospitalized patients, as well as strong T cell responses.…”

Section: Discussionmentioning

confidence: 99%

Phase 1 randomized trial of a plant-derived virus-like particle vaccine for COVID-19

Ward

Gobeil

Séguin

et al. 2021

Nat Med

Self Cite

246

276

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Several severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are being deployed, but the global need greatly exceeds the supply, and different formulations might be required for specific populations. Here we report Day 42 interim safety and immunogenicity data from an observer-blinded, dose escalation, randomized controlled study of a virus-like particle vaccine candidate produced in plants that displays the SARS-CoV-2 spike glycoprotein (CoVLP: NCT04450004). The co-primary outcomes were the short-term tolerability/safety and immunogenicity of CoVLP formulations assessed by neutralizing antibody (NAb) and cellular responses. Secondary outcomes in this ongoing study include safety and immunogenicity assessments up to 12 months after vaccination. Adults (18–55 years, n = 180) were randomized at two sites in Quebec, Canada, to receive two intramuscular doses of CoVLP (3.75 μg, 7.5 μg, and 15 μg) 21 d apart, alone or adjuvanted with AS03 or CpG1018. All formulations were well tolerated, and adverse events after vaccination were generally mild to moderate, transient and highest in the adjuvanted groups. There was no CoVLP dose effect on serum NAbs, but titers increased significantly with both adjuvants. After the second dose, NAbs in the CoVLP + AS03 groups were more than tenfold higher than titers in Coronavirus 2019 convalescent sera. Both spike protein-specific interferon-γ and interleukin-4 cellular responses were also induced. This pre-specified interim analysis supports further evaluation of the CoVLP vaccine candidate.

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Section: Discussionmentioning

confidence: 99%

Phase 1 randomized trial of a plant-derived virus-like particle vaccine for COVID-19

Ward

Gobeil

Séguin

et al. 2021

Nat Med

Self Cite

246

276

View full text Add to dashboard Cite

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“…Even with these resource-intensive measures in place, it is not possible to exclude the risk of VED altogether – in other words there will often be residual uncertainty – and trials of COVID-19 vaccines have involved informing volunteers regarding the risks and uncertainties related to VED 47 . Fortunately, no cases of COVID-19 VED have been documented in phase I-III trial participants 1 , yet this does not exclude the possibility of delayed disease enhancement in the context of waning immune responses. Clinicians and public health agencies should therefore thoroughly investigate any unusually severe cases of COVID-19 in vaccine recipients, ideally using recently proposed standardized criteria for the detection and confirmation of VED 1 .…”

Section: Ethical Implicationsmentioning

confidence: 99%

“…Vaccine-enhanced disease (VED) is a distinct type of infection-related adverse event that occurs when disease severity is increased following exposure to the relevant pathogen after vaccination 1 . A key difference between VED and other adverse events is that it is contingent on post-vaccination infection with the relevant pathogen, whereas other types of adverse events are caused by the vaccine itself (including in rare cases where the microbes in live-attenuated vaccines themselves cause disease) or direct immune responses to the vaccine.…”

Section: Introductionmentioning

confidence: 99%

“…A key difference between VED and other adverse events is that it is contingent on post-vaccination infection with the relevant pathogen, whereas other types of adverse events are caused by the vaccine itself (including in rare cases where the microbes in live-attenuated vaccines themselves cause disease) or direct immune responses to the vaccine. Other authors have provided guidance for the detection of a correlation between vaccination and increased disease severity and the confirmation of likely VED with additional evidence supporting a causal link between vaccination and enhanced disease 1 .…”

Section: Introductionmentioning

confidence: 99%

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Vaccine-enhanced disease: case studies and ethical implications for research and public health

et al. 2021

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Vaccination is a cornerstone of global public health. Although licensed vaccines are generally extremely safe, both experimental and licensed vaccines are sometimes associated with rare serious adverse events. Vaccine-enhanced disease (VED) is a type of adverse event in which disease severity is increased when a person who has received the vaccine is later infected with the relevant pathogen. VED can occur during research with experimental vaccines and/or after vaccine licensure, sometimes months or years after a person receives a vaccine. Both research ethics and public health policy should therefore address the potential for disease enhancement. Significant VED has occurred in humans with vaccines for four pathogens: measles virus, respiratory syncytial virus, Staphylococcus aureus, and dengue virus; it has also occurred in veterinary research and in animal studies of human coronavirus vaccines. Some of the immunological mechanisms involved are now well-described, but VED overall remains difficult to predict with certainty, including during public health implementation of novel vaccines. This paper summarises the four known cases in humans and explores key ethical implications. Although rare, VED has important ethical implications because it can cause serious harm, including death, and such harms can undermine vaccine confidence more generally – leading to larger public health problems. The possibility of VED remains an important challenge for current and future vaccine development and deployment. We conclude this paper by summarising approaches to the reduction of risks and uncertainties related to VED, and the promotion of public trust in vaccines.

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“…Despite progress on early ambulatory, multidrugtherapy for high-risk patients, resulting in 85% reductions in COVID-19 hospitalization and death [1], the current paradigm for control is mass-vaccination. While we recognize the effort involved in development, production and emergency authorization of SARS-CoV-2 vaccines, we are concerned that risks have been minimized or ignored by health organizations and government authorities, despite calls for caution [2][3][4][5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 mass vaccination: Urgent questions on vaccine safety that demand answers from international health agencies, regulatory authorities, governments and vaccine developers

Acevedo‐Whitehouse¹,

Bruno²,

McCullough

et al. 2021

Preprint

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Since the start of the COVID-19 outbreak, the race for testing new platforms designed to confer immunity against SARS-CoV-2, has been rampant and unprecedented, leading to conditional emergency authorization of various vaccines. Despite progress on early multidrug therapy for COVID-19 patients, the current mandate is to immunize the world population as quickly as possible. The lack of thorough testing in animals prior to clinical trials, and authorization based on safety data generated during trials that lasted less than 3.5 months, raise questions regarding vaccine safety. The recently identified role of SARS-CoV-2 Spike glycoprotein for inducing endothelial damage characteristic of COVID-19, even in absence of infection, is extremely relevant given that most of the authorized vaccines induce endogenous production of Spike. Given the high rate of occurrence of adverse effects that have been reported to date, as well as the potential for vaccine-driven disease enhancement, Th2-immunopathology, autoimmunity, and immune evasion, there is a need for a better understanding of the benefits and risks of mass vaccination, particularly in groups excluded from clinical trials. Despite calls for caution, the risks of SARS-CoV-2 vaccination have been minimized or ignored by health organizations and government authorities. As for any investigational biomedical program, data safety monitoring boards (DSMB) and event adjudication committees (EAC), should be enacting risk mitigation. If DSMBs and EACs do not do so, we will call for a pause in mass vaccination. If DSMBs and EACs do not exist, then vaccination should be halted immediately, in particular for demographic groups at highest risk of vaccine-associated death or serious adverse effects, during such time as it takes to assemble these boards and commence critical and independent assessments. We urge for pluralistic dialogue in the context of health policies, emphasizing critical questions that require urgent answers, particularly if we wish to avoid a global erosion of public confidence in science and public health.

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Vaccine-associated enhanced disease: Case definition and guidelines for data collection, analysis, and presentation of immunization safety data

Cited by 80 publications

References 129 publications

Phase 1 randomized trial of a plant-derived virus-like particle vaccine for COVID-19

Phase 1 randomized trial of a plant-derived virus-like particle vaccine for COVID-19

Vaccine-enhanced disease: case studies and ethical implications for research and public health

SARS-CoV-2 mass vaccination: Urgent questions on vaccine safety that demand answers from international health agencies, regulatory authorities, governments and vaccine developers

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