Health economic analyses of secondary vaccine effects: a systematic review and policy insights

Figures & data

Table 1. Definitions of some terms associated with different fields/domains and our definitions for terms related to defining economics of secondary vaccine effects

Term	Existing definition(s) [source]	Our definition (if used)
Clinical immunology/basic science
Primary vaccine effect (PVE)	(1) “Antigen-specific protection and memory in adaptive immune cells throughout the body” [31] (2) “Immune response to protect against specific disease targets” [40]	Activation of the antigen-specific (or pathogen-specific) systemic or local adaptive immunity subsequent to the administration of a vaccine
Secondary vaccine effect (SVE)	(1) “Unintended consequences or collateral benefits … beyond what would be expected due to primary antigen-specific protective effects” [31] (2) “Any effect of a given vaccine, other than the intended effect of preventing disease caused by the specific pathogen they were designed to protect against” [40]	The set of all immunological responses to a vaccine that are not a direct consequence of the antigen-specific (or pathogen-specific) activation of the adaptive immunity
Patient safety/pharmacovigilance
Side effect	(1) “Any unintended effect of a pharmaceutical product occurring at doses normally used in humans which is related to the pharmacological properties of the medicine.” [41] (2) “Side effects, also known as adverse events, are unwanted or unexpected events or reactions to a drug” [42] (3) “Any unintended effect of a pharmaceutical product (including vaccines) occurring at a dose normally used in man” [43]
Adverse (drug) reaction	(1) “An adverse reaction to a drug is one that is noxious, is unintended, and occurs at a dose normally used in man.” [44] (2) “An undesirable side effect that occurs after a vaccination” and may be “1) local, 2) systemic, or 3) allergic.” [45] (3) “Adverse reactions, also known as side effects, are considered to be caused by a vaccine. Usually, vaccine side effects are identified during clinical trials.” [46] (4) “Any adverse event for which there is a reasonable possibility that the drug caused the adverse event.” [47]
Adverse event	(1) “Side effects, also known as adverse events, are unwanted or unexpected events or reactions to a drug.” [42] (2) “Adverse event means any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related” [47]
Adverse event following immunization (AEFI)	“Any untoward medical occurrence which follows immunization and which does not necessarily have a causal relationship with the usage of the vaccine” [38]	Any unintended harmful effect that follows immunization (including administration) and which does not necessarily have a causal relationship with the usage of the vaccine
Beneficial event following immunization (BEFI)		Any unintended beneficial effect that follows immunization (including vaccine administration) and which does not necessarily have a causal relationship with the usage of the vaccine
Health economics
Economics of Primary Vaccine Effects (ePVEs)		Any health outcomes associated with the pathogen with sufficient evidence for quantification and that may be prevented or reduced by use of the vaccine as intended for its primary disease target and all quantifiable associated AEFIs and BEFIs
Economics of Secondary Vaccine Effects (eSVEs)		Any unintended health outcomes characterized by the study as SVEs, including or non-antigen specific effects and/or use for a secondary disease target

Figure 1. Schematic overview of the underlying mechanisms for primary and secondary vaccine effects. Primary vaccine effects (PVEs) are almost exclusively under the umbrella of the adaptive immunity. As shown in the right panel, these effects are mediated through antigen-dependent activation of naïve B and T cells, ultimately resulting in production of antibodies by mature plasma cells, as well as the development of CD4+ helper and CD8+ cytotoxic T cells. Memory B and T cells (not shown) expedite production of activated B and T cells during subsequent exposures to the same antigen. The immunological underpinnings of Secondary Vaccine Effects (SVEs) are not as well established, but emerging evidence points largely to activation and/or training of the antigen-independent innate immunity. Activation of the innate immunity (middle panel) is complex and involves multiple systems, cell types, and chemical signals, a review of which is beyond the scope of this manuscript. Most importantly, the emerging field of the trained immunity (left panel) is thought to be the reason behind the enhanced immune response to various pathogens observed after administration of a specific vaccine. Innate immune memory is best described for cells of the myeloid lineage, including the bone marrow progenitors, through epigenetic modifications, metabolic reprogramming and enhanced cytokine production, collectively giving the innate immune system a so-called ‘defensive’ posture against pathogens. A minor component of SVEs may also be mediated secondarily through the adaptive immune system because of antibody cross-reactivity or antigen-mimicry.

Figure 2. Search strategy, exclusions and eligibility criteria used to identify quantitative health economic analyses of secondary vaccine effects (eSVEs) through 1 November 2021.

Table 2. Detailed literature search strategy to retrieve records related to quantitative health economic evaluations of vaccine secondary effects

	Database
Subject	PubMed®	Web of Science®
Vaccines	‘vaccines’[MeSH Terms] OR ‘vaccin*’[All Fields] OR ‘vaccination’[MeSH Terms] OR ‘vaccinat*’[All Fields] OR ‘immunizat*’[All Fields] OR ‘immunisat*’[All Fields] OR ‘immunization’[MeSH Terms]	TI = (vaccin* OR immunizat* OR immunisat*) OR AB = (vaccin* OR immunizat* OR immunisat*)
Economics	‘econ*’[All Fields] AND (‘healt*’[All Fields] OR ‘evaluation’[All Fields])	TS = (econ* ‘and’ healt*) OR (econ* ‘and’ evaluation)
OR	‘cost’[All Fields] AND (‘effect*’[All Fields] OR ‘benefit’[All Fields])	TI = (‘cost effect*’ OR ‘cost benef*’) OR AB = (‘cost effect*’ OR ‘cost benef*’)
Secondary Effects	((nonspecific) OR (non-specific) OR (off-target) OR (heterologous) OR (pathogen agnostic) OR (unintended)) AND (effect*)	TI = ((nonspecific OR non-specific OR heterologous OR off-target OR pathogen-agnostic OR unintended) AND ffect*) OR AB = ((nonspecific OR non-specific OR heterologous OR off-target OR pathogen-agnostic OR unintended) AND effec*)
Filters	English (select) Other Animals (exclude)	English [Language] (select) ‘Animals’[MeSH Headings] (exclude)

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