TY - JOUR

T1 - Implications of Non-Specific Effects for Testing, Approving, and Regulating Vaccines

AU - Benn, Christine Stabell

AU - Amenyogbe, Nelly

AU - Bjorkman, Anders

AU - Dominguez-Andres, Jorge

AU - Fish, Eleanor N.

AU - Flanagan, Katie L.

AU - Klein, Sabra L.

AU - Kollmann, Tobias R.

AU - Kyvik, Kirsten Ohm

AU - Netea, Mihai G.

AU - Rod, Naja Hulvej

AU - Schaltz-Buchholzer, Frederik

AU - Shann, Frank

AU - Selin, Liisa

AU - Thysen, Sanne M.

AU - Aaby, Peter

PY - 2023

Y1 - 2023

N2 - The current framework for testing and regulating vaccines was established before the realization that vaccines, in addition to their effect against the vaccine-specific disease, may also have "non-specific effects" affecting the risk of unrelated diseases. Accumulating evidence from epidemiological studies shows that vaccines in some situations can affect all-cause mortality and morbidity in ways that are not explained by the prevention of the vaccine-targeted disease. Live attenuated vaccines have sometimes been associated with decreases in mortality and morbidity that are greater than anticipated. In contrast, some non-live vaccines have in certain contexts been associated with increases in all-cause mortality and morbidity. The non-specific effects are often greater for female than male individuals. Immunological studies have provided several mechanisms that explain how vaccines might modulate the immune response to unrelated pathogens, such as through trained innate immunity, emergency granulopoiesis, and heterologous T-cell immunity. These insights suggest that the framework for the testing, approving, and regulating vaccines needs to be updated to accommodate non-specific effects. Currently, non-specific effects are not routinely captured in phase I-III clinical trials or in the post-licensure safety surveillance. For instance, an infection with Streptococcus pneumoniae occurring months after a diphtheria-tetanus-pertussis vaccination would not be considered an effect of the vaccination, although evidence indicates it might well be for female individuals. Here, as a starting point for discussion, we propose a new framework that considers the non-specific effects of vaccines in both phase III trials and post-licensure.

AB - The current framework for testing and regulating vaccines was established before the realization that vaccines, in addition to their effect against the vaccine-specific disease, may also have "non-specific effects" affecting the risk of unrelated diseases. Accumulating evidence from epidemiological studies shows that vaccines in some situations can affect all-cause mortality and morbidity in ways that are not explained by the prevention of the vaccine-targeted disease. Live attenuated vaccines have sometimes been associated with decreases in mortality and morbidity that are greater than anticipated. In contrast, some non-live vaccines have in certain contexts been associated with increases in all-cause mortality and morbidity. The non-specific effects are often greater for female than male individuals. Immunological studies have provided several mechanisms that explain how vaccines might modulate the immune response to unrelated pathogens, such as through trained innate immunity, emergency granulopoiesis, and heterologous T-cell immunity. These insights suggest that the framework for the testing, approving, and regulating vaccines needs to be updated to accommodate non-specific effects. Currently, non-specific effects are not routinely captured in phase I-III clinical trials or in the post-licensure safety surveillance. For instance, an infection with Streptococcus pneumoniae occurring months after a diphtheria-tetanus-pertussis vaccination would not be considered an effect of the vaccination, although evidence indicates it might well be for female individuals. Here, as a starting point for discussion, we propose a new framework that considers the non-specific effects of vaccines in both phase III trials and post-licensure.

KW - DIPHTHERIA-TETANUS-PERTUSSIS

KW - TITER MEASLES IMMUNIZATION

KW - BCG VACCINATION

KW - MALE MORTALITY

KW - GUINEA-BISSAU

KW - SEX

KW - FEMALE

KW - TRIALS

KW - INFANTS

KW - POLIO

U2 - 10.1007/s40264-023-01295-3

DO - 10.1007/s40264-023-01295-3

M3 - Journal article

C2 - 37074598

VL - 46

SP - 439

EP - 448

JO - Drug Safety

JF - Drug Safety

SN - 0114-5916

ER -