Table 2.
Target product profile for Ebola vaccines in epidemic and endemic settings
|
Prevention of EVD in the current or future epidemics (reactive use)* |
Protection against endemic EVD (prophylactic use) |
|||
|---|---|---|---|---|
| Optimal | Minimal | Optimal | Minimal | |
| Criteria applicable to characteristics of Ebola vaccines | ||||
| Indication for use | For active immunisation of at-risk people residing in the area of the current epidemic or in a future outbreak area; to be used in conjunction with other control measures to curtail or end an outbreak | For active immunisation of at-risk people residing in the area of the current epidemic or in a future outbreak area; to be used in conjunction with other control measures to curtail or end an outbreak | For active immunisation of people considered at high risk of EVD based on specific risk factors (such as occupation) or based on residence in a geographic area at risk for EVD | For active immunisation of people considered at high risk of EVD based on specific risk factors (such as occupation) or based on residence in a geographic area at risk for EVD |
| Target population | The vaccine can be given to all age groups and populations, including special populations (immunocompromised people, pregnant women, people with underlying chronic disease, and malnourished people)†,‡ | The vaccine can be given to healthy older adolescents and non-pregnant adults§ | The vaccine can be given to all age groups and populations, including special populations (immunocompromised people, pregnant women, people with underlying chronic disease, and malnourished people)†,‡ | The vaccine can be given to healthy older adolescents and non-pregnant adults¶ |
| Safety‖ | A safety profile that is consistent with expectations for a licensed vaccine and, if the vaccine is efficacious, will provide a highly favourable risk-benefit ratio, ideally with only mild or transient side-effects (ie, grade 1 AEs) and lacks evidence of serious AEs** If fever is an AE, it should be of short duration (preferably resolving within 24 h) |
A safety profile that is consistent with expectations for a licensed vaccine and, if the vaccine is efficacious, will provide a favourable risk-benefit ratio (primarily grade 1 AEs, with grades 2–4 AEs occurring rarely)** | Robust safety profile whereby vaccine benefit clearly outweighs any safety concerns Safety profile demonstrates only mild transient health effects (ie, grade 1 AEs) and lacks evidence of serious AEs**,‡ |
Robust safety profile whereby vaccine benefit clearly outweighs any safety concerns Safety profile demonstrates primarily mild transient health effects (ie, grade 1 AEs) and serious AEs (grades 2–4) are rare** |
| Efficacy/effectiveness | Interrupts disease transmission Greater than 90% efficacy in preventing disease in healthy children and adults§ Rapid onset of immunity Evidence for post-exposure efficacy in primate challenge experiments |
Greater than 50% efficacy in preventing disease in healthy older adolescents and adults§ Rapid onset of immunity |
Greater than 90% efficacy or effectiveness in preventing disease in healthy children and adults | Greater than 50% efficacy or effectiveness in preventing disease in healthy older adolescents and adults§ |
| Dose regimen | Single-dose regimen | Prime-boost regimen with booster dose no more than 1 month after initial dose | Single-dose regimen | Single-dose regimen or prime-boost regimen with additional booster doses as needed Booster dose schedule is designed to achieve optimal long-term protection |
| Durability of protection | Confers at least 2 years of protection†† | Confers at least 3 to 6 months of protection†† | Confers longlasting protection of 10 years or more (with booster doses as necessary to maintain durability over time) †† | Confers at least 2 years of protection after completion of the vaccination regimen†† |
| Criteria applicable for production and distribution of Ebola vaccines | ||||
| Route of administration | Injectable (intramuscular, intradermal, or subcutaneous) or other formulation, such as ingestible, nasal, or transdermal patch, if available | Injectable (intramuscular, intradermal, or subcutaneous) or other formulation as available | Injectable (intramuscular, intradermal, or subcutaneous) or other formulation, such as ingestible, nasal, or transdermal patch, if available | Injectable (intramuscular, intradermal, or subcutaneous) or other formulation as available |
| Formulation | Monovalent vaccine effective against Zaire Ebola virus‡‡ Does not require an adjuvant |
Monovalent vaccine effective against Zaire Ebola virus‡‡ | Trivalent vaccine effective against Zaire Ebola virus, Sudan Ebola virus, and Marburg virus Does not require an adjuvant |
Monovalent vaccines effective against Zaire Ebola virus, Sudan Ebola virus, and Marburg virus |
| Product stability and storage | Shelf life of at least 36 months Does not require storage at −80°C to prevent degradation The need for a preservative is determined and any issues are addressed Product is stable at refrigeration temperatures (2–8°C) Heat stability should be maximised to allow product to be used in a CTC (ie, with storage out of cold chain at room temperature for up to several days) |
Shelf life of at least 12 months The need for a preservative is determined and any issues are addressed Storage conditions comply with cold-chain capabilities; product may be stored at −80°C or at −20°C, if stable for some period of time (hours to a few days) at 2–8°C or at room temperature (to allow for shipment and storage in the field) |
Shelf life of at least 36 months Does not require storage at −80°C to prevent degradation The need for a preservative is determined and any issues are addressed Product is stable at refrigeration temperatures (2–8°C) Heat stability should be maximised to allow product to be used in a CTC (ie, with storage out of cold chain at room temperature for up to several days) |
Shelf life of at least 24 months The need for a preservative is determined and any issues are addressed Storage conditions comply with cold-chain capabilities; product may be stored at −80°C or at −20°C, if stable for some period of time (hours to a few days) at 2–8°C or at room temperature (to allow for shipment and storage in the field) |
| Coadministration with other vaccines | The vaccine will be given as a stand-alone product not coadministered with other vaccines | The vaccine will be given as a stand-alone product not coadministered with other vaccines | The vaccine can be coadministered with other licensed vaccines without clinically significant impact on immunogenicity or safety | The vaccine will be given as a stand-alone product not coadministered with other vaccines. |
| Presentation | In an outbreak setting, the simplest presentation is likely best (ie, a mono-dose, liquid product that does not require reconstitution); however, other options noted in the bullets below are acceptable. Vaccine is provided as a liquid or lyophilised product in mono-dose or low multi-dose (10–20) presentations§§,¶¶ Multi-dose presentations should be formulated, managed, and discarded in compliance with multi-dose vial policies Lyophilised vaccine will need to be accompanied by paired separate vials of the appropriate diluent |
Vaccine is provided as a liquid or lyophilised product in mono-dose or low multi-dose (10–20) presentations§§,¶¶ Multi-dose presentations should be formulated, managed, and discarded in compliance with multi-dose vial policies Lyophilised vaccine will need to be accompanied by paired separate vials of the appropriate diluent |
Vaccine is provided as a liquid or lyophilised product in mono-dose or low multi-dose (10–20) presentations§§,¶¶ Multi-dose presentations should be formulated, managed, and discarded in compliance with multi-dose vial policies Lyophilised vaccine will need to be accompanied by paired separate vials of the appropriate diluent |
Vaccine is provided as a liquid or lyophilised product in mono-dose or low multi-dose (10–20) presentations§§,¶¶ Multi-dose presentations should be formulated, managed, and discarded in compliance with multi-dose vial policies Lyophilised vaccine will need to be accompanied by paired separate vials of the appropriate diluent |
| Production | Can be produced efficiently and as expeditiously as possible after a validated scale-up that allows for maximum production yields; the dose of antigen required for protection allows for high production yield (which will affect cost and availability) 5 million doses can be produced by the end of 2015 (for the current epidemic) Ideally, production involves a single bulk-substance product (without requiring a separate booster product or diluent [needed for lyophilised vaccines]) If a booster with an alternative product is needed, that product also can be produced quickly and without substantial manufacturing barriers or supply-chain issues If an adjuvant is needed, it can be formulated with the vaccine instead of combined at the time of use |
The dose of antigen required for protection allows for high production yield (which will affect cost and availability) 5 million doses can be produced during 2016 (for the current epidemic) If a booster with an alternative product is needed, that product also can be produced quickly and without significant manufacturing barriers or supply-chain issues |
Can be produced efficiently and as expeditiously as possible; the dose of antigen required for protection allows for high production yield (which will affect cost and availability) Can be produced in quantities sufficient for prophylactic use in at-risk regions or populations If a booster with an alternative product is needed, that product also can be produced quickly and without significant manufacturing barriers or supply-chain issues If an adjuvant is needed, it can be formulated with the vaccine instead of combined at the time of use |
Can be produced in quantities sufficient for prophylactic use in at-risk regions or populations |
| Licensure | Meets criteria for licensure or accelerated licensure pathway Recommendation for vaccine use by the WHO |
Meets criteria for accelerated licensure pathway or expanded access (such as EUA), with full licensure potentially to follow‖‖ Criteria for expanded access or EUA are acceptable to EMA, FDA, and the NRAs of countries affected by the epidemic‖‖ Conditional recommendation for vaccine use by the WHO |
Meets criteria for licensure Product is prequalified by the WHO |
Meets criteria for licensure |
AE=adverse event. CTC=controlled temperature chain. EMA=European Medicines Agency. EUA=emergency use authorisation (applicable to regulations in the USA). EVD=Ebola virus disease. FDA=US Food and Drug Administration. NRA=national regulatory authority.
Optimal and minimal criteria for vaccines to be used in the current epidemic are similar to considerations for vaccines that may be used in future outbreaks or epidemics if a reactive vaccination strategy is employed. Vaccines developed and produced now or in the future may be stockpiled for reactive use in future situations.
Optimally, a vaccine should be available for all age groups; however, some vaccines might not be able to be given to young children because of general reactogenicity or interference with safety or efficacy of EPI (Expanded Program on Immunization) vaccines.
Ideally, a vaccine will be safe and effective in special populations, such as immunocompromised people or pregnant women; however, obtaining efficacy and safety data for such populations will require special studies that take extensive time to design and conduct; therefore, this feature is not realistic for the current epidemic, but may be a consideration for a future time, if appropriate.
Initial vaccination of older adolescents and adults is a potentially viable strategy because: this will encompass most high-risk people (eg, health-care workers, Ebola community workers, funeral workers, and in-home care providers as well as many case contacts); the epidemiology of EVD in west Africa indicates that the largest burden of disease occurs in this age group, and by targeting this population, enough herd immunity might be achieved to stop the outbreak when combined with other control measures.
A tiered strategy targeted initially to health-care workers, adults, and adolescents, then later to children and the elderly over time might be considered (depending on the vaccination strategy), with more than one vaccine product being appropriate for different populations and different usages.
Safety profiles for vaccines used in an outbreak/epidemic setting might potentially be lower than the safety profiles for vaccines used on a prophylactic basis to prevent endemic disease or future outbreaks, since the risk/benefits in the two settings may be different.
A system for grading adverse events is as follows. Grade 1 (mild): symptoms cause no or minimal interference with usual social and functional activities; grade 2 (moderate): symptoms cause greater than minimal interference with usual social and functional activities; grade 3 (severe): symptoms cause inability to perform usual social and functional activities; grade 4 (potentially life threatening): symptoms cause inability to perform basic self-care functions, or a medical or operative intervention is indicated to prevent permanent impairment, persistent disability, or death.
Investigators will not be able to determine durability of protection in the current clinical trials; this will require additional observation and follow-up studies.
A monovalent vaccine against Zaire Ebola virus is adequate to control the current west Africa epidemic; however, strategic use of a reactive vaccination strategy aimed at controlling future filovirus disease outbreaks will likely also require development of monovalent vaccines against Sudan Ebola virus and Marburg virus or a trivalent vaccine against all three pathogens.
Liquid vaccines are easy to administer because they don't need reconstitution. Lyophilised vaccines may be more temperature stable, but require reconstitution with an appropriate diluent. These two different forms of vaccine each have advantages and disadvantages that will need to be weighed based on conditions in the field, including stability, transport, and disposal constraints.
Single-dose vials potentially decrease safety risks. Single-dose or low multi-dose vials also decrease vaccine wastage, which is an important factor when considering cost of administration; however, they require increased storage space. The optimal number of doses per vial, therefore, will need to take into consideration field conditions and the vaccination strategy (eg, 50 or more doses per vial may be appropriate for a mass vaccination strategy).
Issues around accelerated licensure and expanded access apply predominantly to this epidemic. If the current phase 3 clinical disease endpoint studies are inconclusive, one or more Ebola vaccines could potentially be licensed via FDA's accelerated approval pathway (if correlates of protection are identified) or via FDA's Animal Rule pathway (if correlates of protection cannot be identified).