4.1 Vaccine safety2 (1).pdf

4. Vaccine safety Overview 1. Importance of vaccine safety 2. Vaccine side effects 3. Methods to evaluate vaccine safety 4. Pathogenesis of vaccine-induced sides effects + Some examples of hypothetical, unproven associations between vaccines en diseases ➔ vaccine criticism, vaccine hesitancy, vac...

4. Vaccine safety Overview 1. Importance of vaccine safety 2. Vaccine side effects 3. Methods to evaluate vaccine safety 4. Pathogenesis of vaccine-induced sides effects + Some examples of hypothetical, unproven associations between vaccines en diseases ➔ vaccine criticism, vaccine hesitancy, vaccine refusal, anti-vaccine movement 2 Overview 1. Importance of vaccine safety 2. Vaccine side effects 3. Methods to evaluate vaccine safety 4. Pathogenesis of vaccine-induced sides effects + Some examples of hypothetical, unproven associations between vaccines en diseases ➔ vaccine criticism, vaccine hesitancy, vaccine refusal, anti-vaccine movement 3 Importance of vaccine safety “Primum non nocere” - “First of all, cause no harm” is one of the basic principles of bioethics (Hippocrates’ oath) Every intervention (in casu vaccination) must have a favorable risk/benefit ratio A vaccine is not a common drug Vaccines are administered to prevent disease: • To healthy people, to infants in particular •To extremely large numbers of people in vaccination campaigns • Sometimes mandatory Medicines are given to treat disease: • To sick people •Side effects (even severe ones) are accepted when the disease to be treated is very serious or deadly (e.g. cancer) Reverse side of the safety coin Vaccines and vaccination become the victim of their own success. Diseases against which we vaccinate become increasingly rare or even disappear completely, while adverse events (mainly minor, sometimes more severe) lower the confidence in vaccines. Lowering vaccine coverage can lead to reappearance of a disease that was considered to be under control or even conquered. In the past 70 years several infectious diseases have been successfully prevented and one even eradicated Cases 530217 -> 55 Deaths 440 -> 0 Cases 21053 -> 0 Deaths 1822 -> 0 Cases 162344 -> 6584 Deaths 440 -> 0 Cases 152 -> 11 Deaths ? -> 0 Cases 580 -> 41 Deaths 472 -> 4 Roush et al. JAMA. 2007;298(18):2155-2163 Side effects of a vaccine can jeopardize a vaccination program Prevaccine Increasing coverage Loss of confidence Resumption Eradication of confidence Disease Vaccine coverage Outbreak Adverse effects Eradication Example: Pertussis vaccination in the USA (1940-2002) 250000 Start of vaccination Cases 200000 150000 100000 50000 0 1940 1950 1960 1970 1980 1990 2000 Example: Pertussis vaccination in the USA (1980 -2002) Side effects of the whole cell pertussis vaccine (Pw) 12000 10000 Cases 8000 • Fever exceeding 40,5 °C • Convulsions without or with fever • Persistent crying • Cyanosis • Hypotonic hyporesponsive episodes • Shock 6000 4000 2000 0 1980 1985 1990 1995 2000 Overview 1. Importance of vaccine safety 2. Vaccine side effects 3. Methods to evaluate vaccine safety 4. Pathogenesis of vaccine-induced sides effects + Some examples of hypothetical, unproven associations between vaccines en diseases ➔ vaccine criticism, vaccine hesitancy, vaccine refusal, anti-vaccine movement 11 Side effects of vaccination Immediate onset side effects (hours, days) Late onset side effects •Common local and general adverse events •Vary according to the vaccine • Anaphylaxis (+/- 1:1 000 000): type I hypersensitivity, possibly with bronchospasm and shock •Varies according to the vaccine (several days or weeks) • Causality needs to be proven Common adverse events of vaccines Local adverse events (at the injection site): • Pain • Swelling • Redness Systemic adverse events • Fever • Chills • Fatigue • Headache • Myalgia, arthralgia • Malaise Generally mild to moderate in intensity and transient (disappearing spontaneously after +/- 24-72u) Reactogenicity score – radar plot Reactogenicity AS01B AS01E 100 % AS03 50 0 AS04 Alum Any grade Grade 1 Grade 2 Leroux-Roels G, et al Clin Immunol. 2016;169:16–27 Immediate type hypersensitivity reactions (type I) Anaphylaxis: a rare, but very serious event Frequency • ± 1 per million vaccine doses • mRNA vaccines: 2-5/million doses (increased incidence most likely caused by an excipient) Cave evolution to anaphylactic shock! Treatment of anaphylactic shock • Recognize an anaphylactic reaction (from other events) • Immediately call the the emergency service (112) • ABC of resuscitation • Adrenalin is 1st choice medication Arthus reaction (type III) A rare type III hypersensitivity reaction Following vaccination with tetanus (T) or diphtheria (D) vaccine Local vasculitis due to precipitation of immune complexes Symptoms: severe pain, swelling, induration, edema, 4–12 hours after vaccination. Advice: do not administer a booster dose within a period of 10 years Delayed type hypersensitivity reaction (type IV) “The Moderna arm” Blumenthal et al. N Engl J Med 2021; 384: 1273-77 -Series of delayed cutaneous reactions -Median time of onset: 8 days (range 4 to 11 days) -Delayed type or T-cell mediated hypersensitivity reaction: skin biopsy showed superficial perivascular and perifollicular lymphocytic infiltrates with rare eosinophils and scattered mast cells Blumenthal et al. N Engl J Med 2021; 384: 1273-77 Summary of hypersensitivity reactions Sampath et al. Allergy 2021; https://doi.org/10.1111/all.14840 Side effects of vaccination: some proven, vaccinespecific side effects. Adverse event/side effect Vaccine Frequency Pustle formation and scarring Cowpox vaccine 100% (proof of ‘vaccine take’) Rash MMR(-V) ± 3:100 Arthus reaction (type III hypersensitivity reaction) Tetanus and diphteria toxoid ? (rare) Anaphylaxis (type I hypersensitivity reaction) All < 1:1 000 000 Lymphadenitis BCG 1:2600 VAPP (vaccine-associated paralytic polio) OPV 1:2 400 000 (WHO) Intussusception Rotavirus vaccine (Rotashield) 1:11 000 Meningitis Mumps (Urabe Am 9: insufficiently attenuated strain) 1:10 000 Frequencies: FYI FIGURE 1 Mechanisms of vaccine-associated enhanced disease. (A) Antibody-dependent enhancement (ADE) occurs when antibodies increase the ability of a virus to infect cells (also see Figure 2). (B) Antibody-enhanced disease (AED) occurs when antibodies exacerbate inflammation, resulting in pathology (also see Figure 2). (C) Th2-skewed responses can be pathogenic for some infections and so vaccines that induce Th2 responses in this case can cause pathology. Usually Th2 pathology is associated with eosinophil infiltration. (D) Components of vaccine formulations such as bovine serum albumin (BSA) and cellular debris can mediate pathogenic cellular responses to these components when encountered again as contaminants in the challenge material. While these components are normally removed during vaccine preparation, some preclinical studies have not included appropriate washing and centrifugation steps to facilitate this. (E) Immune complexes between viral proteins, antibodies and/or complement can lead to a build-up of deposits in blood vessels and organs or facilitate enhanced uptake of virus through myeloid cells, causing ADE. Both of these outcomes can enhance pathology. Made with BioRender.com. Examples: - Formol inactivated RSV vaccine - Dengue infection Gartlan et al. Front Immunol 2022; https://doi.org/10.3389/fimmu.2022.882972 Overview 1. Importance of vaccine safety 2. Vaccine side effects 3. Methods to evaluate vaccine safety 4. Pathogenesis of vaccine-induced sides effects + Some examples of hypothetical, unproven associations between vaccines en diseases ➔ vaccine criticism, vaccine hesitancy, vaccine refusal, anti-vaccine movement 24 Vaccine safety is of utmost importance Therefore evaluated throughout the full development cycle Pharmacovigilance in EU (EMA) Based on the data of the individual member states. In Belgium: Federal Agency of Medicines and Health Products (FAMPH) Eudravigilance: EMA database Vigibase: WHO database Pharmacovigilance Risk Assessment Committee (PRAC) FYI Post licensure safety monitoring systems in the USA (CDC): passive and active surveillance Vaccine Adverse Event Reporting System (VAERS): • National reporting system • All health care providers and patients can report AEFI (Adverse Event Following Immunization), passive surveillance Vaccine Safety Datalink (VSD) Project: • Collaboration of CDC and 8 healthcare organisations (providing care to 9 million people) • Rigourous monitoring and active evaluation of vaccine safety Clinical Immunization Safety Assessment (CISA) network: • Research on pathophysiology of AEFI, identification of risk factors and development of guidelines for vaccinators FYI Example: How safe are the currently available SARS-CoV-2 vaccines? - To date > 10 billion doses administered, overall a very good safety profile, also in immunocompromised individuals and pregnant women - Mass vaccination: high risk of confounding temporal association with causal association FYI WHO; AEFI: adverse events following vaccination Coincidence ≠ Causality • Temporal association between vaccination and the occurrence of a phenomenon or disease is no proof of causality. Very often it is extremely difficult to demonstrate causality. • During mass vaccination campaigns the risk to confuse coincidence and causality increases. • Diseases occur spontaneously and with certain frequency; this is the background rate To evaluate vaccine safety it is important to know the background rate of a disease Number of coincident events since a vaccine dose Within 1 day Baseline rate Within 7 days Within 6 weeks Guillain-Barré Syndrome (per 10 million of vaccinated people) 0.51 3.58 21.50 1.87 per 100,000 person-years( all ages, UK data) Spontaneous abortions (per million vaccinated pregnant women) 397 2780 16684 Based on data from UK (12% of pregnancies) Sudden death within 1 h of onset of any symptoms (per 10 million vaccinated people) 0.14 0.98 5.75 Based on UK data of 0.5% per 100,00 personyears Black et al. Lancet 2009, 374: 2115-22 To evaluate vaccine safety it is important to know the background rate of a disease Number of coincident events since a vaccine dose Within 1 day Guillain-Barré Syndrome (per 10 million of vaccinated people) 0.51 Baseline rate Within 7 days Within 6 weeks 3.58 21.50 1.87 per 100,000 person-years( all ages, UK data) Number of coinciding cases vaccine Spontaneous when the 397 administered 2780 16684 Based on data abortions (per from UK (12% of would have been a PLACEBO million vaccinated pregnancies) pregnant women) Sudden death within 1 h of onset of any symptoms (per 10 million vaccinated people) 0.14 0.98 5.75 Based on UK data of 0.5% per 100,00 personyears Black et al. Lancet 2009, 374: 2115-22 A complication is probably caused by vaccination when • the effect is biologically acceptable, • experimental or laboratory findings support the causal relationship, • it occurs more frequently in vaccinated persons than in a non-vaccinated control group, or when there is a temporal clustering. Manual: ‘Causality assessment of an adverse event following immunization (AEFI) – WHO User Manual 2013’ (http://www.who.int/vaccine_safety/publications/aevi_manual.pdf) FYI WHO User Manual. Causality assessment of an AEFI. 2013 FYI WHO User Manual. Causality assessment of an AEFI. 2013 Overview 1. Importance of vaccine safety 2. Vaccine side effects 3. Methods to evaluate vaccine safety 4. Pathogenesis of vaccine-induced sides effects + Some examples of hypothetical, unproven associations between vaccines en diseases ➔ vaccine criticism, vaccine hesitancy, vaccine refusal, anti-vaccine movement 38 Pathogenesis of adverse events caused by vaccination 1. Administration process (injection) 2. Contamination 3. Replication of the vaccine antigen 4. Direct effect of a vaccine component 5. Immune response to a vaccine component 6. Unknown cause(s) Vaccine-related factors that can influence the risk for unwanted adverse events (AE) 1. Vaccine type: live-attenuated, inactivated, subunit, .. 2. Strain 3. Attenuation 4. Dose 5. Adjuvant 6. Preservatives 7. Stabilising agents 8. Purity 9. Administration route 10. Co-administration with other vaccines Host-related factors that can influence the risk for adverse events (AE) Age Sex Preceding vaccine doses Preceding infection(s) with the vaccine agent Skin color Pre-existing hypersensitiviy Immune deficiency Genetic factors Courtesy of Prof. Neal Halsey, John Hopkins Bloomberg School of Public Health Courtesy of Prof. Neal Halsey, John Hopkins Bloomberg School of Public Health Injection-related adverse event: syncope Syncope can cause •Injuries by falling down, e.g. head trauma with neurologic sequellae •Traffic accident •Death (rarely) ➔ Precautionary measures: • Evaluate anxiety level of vaccine recipient • Vaccinate in lying position when needed • At least 15 minute observation period following vaccination. Correct injection site in the deltoid muscle Vaccine recipient puts his hand on the hip, this results in an abduction of 60° Vaccinator • puts the index on the acromion • thumb on the tuberositas deltoidea • the ideal injection site is midway • Less chance to damage the bursa, and important nerves (N. axillaris and N. radialis) Cook. Human Vaccine 2011; 7: 845-8 Injection-related adverse event: incorrect injection site Dr. Jonas Salk Damage of the N. ulnaris following anthrax vaccination (Sever et al. Pharmacoepidemiology and Drug Safety 2002) Injection-related adverse event: incorrect injection site Incorrect administration of tetanus toxoid (Source: Unicef website 2007-2009) Injection-related adverse event: incorrect injection site Uchida . Vaccine 2012 (Bursitis after HPV vaccination) Suitable intramuscular injection sites www.immunize.org Use of incorrect diluent • • • • Lyophilized vaccines need to be dissolved in a diluent (sterile physiological solution), in particular in low income countries where multidose vials are used. Cases of respiratory arrest and death following BCG and measles vaccination Paralyzing agents (e.g. succinylcholine, or pancuronium bromide) have been erroneously used as vaccine diluents Diluent and medication vial had identical shape, color and comparable label and were kept in the same cabinet Weekly Epidemiol Record 1996; 71: 239 • 15 children died due to the erroneous usage of curare for the reconstitution of measles vaccine • The vaccination campaign was interrupted for several months Lancet 2014; 384: 1172 Microbial contamination of vaccines Contamination during the production process or during the administration (multidose vials) A few examples: • 1800-1900s Smallpox vaccination: inoculation from arm to arm caused transmission of bacteria, sepsis and syphilis. • 1942 Yellow fever vaccination: contaminated human serum used as stabilizer caused ±28 000 cases of viral hepatitis (HBV) • 1960s Polio vaccines: a few early polio vaccine lots were contaminated with SV40 (oncogenic virus, production in green monkey kidney cells) • 1980s Plasma-derived hepatitis B vaccine: concern about contamination with viruses unknown at that time (HIV, HCV) • 1990s Different vaccines contain gelatin as a stabilizer that could be derived from cattle with BSE (bovine spongiform encephalopathy) Inadequate attenuation of the vaccine strain • 1955 ‘The Cutter Incident’: inadequately inactivated poliovirus administered to 200 000 persons caused 260 cases of paralytic poliomyelitis, of which 10 died Replication of the vaccine antigen Smallpox vaccination: inoculation, pustle formation and scarring Rash after MMR(-V) vaccination (± 3:100) Lymphadenitis after BCG vaccination (± 1:2600) Vaccine-associated paralytic polio (VAPP) • by genetic modification of the vaccine strain (OPV) = vaccine derived polio virus (VDPV) • 1 case per 2 400 000 doses administered • In vaccine recipients and close, unprotected contacts • Also spread via the environment = circulating VDPV (cVDPV) • 250 – 500 cases worldwide, annually • Risk factors: Age > 18 years B cell immune deficiency http://www.who.int/immunization/diseases/poliomyelitis/endgame_objective2/oral_polio_vaccine/VAPPandcVDPVFactSheet-Feb2015.pdf https://polioeradication.org/polio-today/polio-now/ Rotavaccine (RotaShield) and intussusception = part of the intestine folds into the section next to it Mechanism unknown: possibly by oedema or lymphoid hyperplasia Linked to first licensed rotavirus vaccine ‘Rotashield’ • Incidence: 10-20/100 000 (RR 20-30) • Clustering: <2 weeks following dose 1 (dose 2) • 1-2 extra cases per 10 000 doses • Not noticed during the clinical development • Registration in 1997 → removed from the market in 1998 ➔ Consequence for the next RV vaccines: huge clinical trials involving very large numbers of participants were required (60 000 – 70 000). Incidence of intussusception • Rotarix: 1-2/100 000 • Rotateq: 1-2/100 000 RR: relative risk Patel. Exp Rev Vaccines 2009; 8: 1555-64 Examples of safety signals linked to SARS-CoV-2 vaccines - Increased incidence of anaphylaxis linked to mRNA vaccines - Bell’s palsy linked to mRNA vaccine - Facial swelling in patients with dermal fillers linked to mRNA vaccines - Myocarditis/pericarditis linked to mRNA vaccines, in particular in young males - Vaccine induced thrombotic thrombocytopenia (VITT)/ thrombosis with thrombocytopenia syndrome (TTS) linked to adenoviral vector vaccines (AstraZeneca, J&J) Increase awareness among the general public and treating physicians → report suspected cases (pharmacovigilance) Cirillo et al. Lancet Infect Dis 2021; CDC, EMA KCE. TTS risk contextualisation for J&J vaccine FYI https://www.hematology.org/covid-19/vaccine-induced-immune-thromboticthrombocytopenia https://www.ema.europa.eu/en/events/ema-workshop-thrombosisthrombocytopenia-syndrome Risk-benefit ratio of Vaxzevria™: number of ICU admissions prevented vs cases of blood clots with low platelets FYI April 2021: PRAC (EMA): benefits outweigh the risks; vaccines can still be used. Member states can decide how the vaccines are used. Increase awareness. e.g. Belgium: Vaxzevria™ and J&J vaccine recommended only for individuals aged 41 and above; those above 41 who received 1 dose of Vaxzevria can receive a second dose. Update recommendation: Vaxzevria and J&J vaccines are not recommended anymore and not available anymore in Belgium (sufficient mRNA vaccines available) https://www.ema.europa.eu/en/documents/chmp-annex/annex-vaxzevria-art53-visual-risk-contextualisation_en.pdf FYI https://www.fagg.be/nl/menselijk_gebruik/geneesmiddelen/geneesmiddelen/covid_19/vaccins/geneesmiddelenbewaking_voor_covid Can vaccination cause autoimmune diseases? Example: Guillain-Barré syndrome (GBS) • Immune-mediated polyradiculopathy with acute ascending paralysis • Mechanism: cellular and humoral immune responses following antigenic stimulation cause damage of nerve cells (e.g. Campylobacter infection, influenza infection) • Link with influenza vaccination dates back from 1976-77 (Swine flu outbreak in VS): 1 additional case per 100 000 administered doses • Background rate: 1-2 cases per 100 000 administered doses/year • Seasonal influenza vaccination: max. 1-2 cases per 1 million administered doses • Risk of GBS after influenza infection is much higher (17/1 million) Overall no increased risk of developing an autoimmune disease after vaccination (hypothetical associations, see further) https://www.cdc.gov/vaccinesafety/concerns/guillain-barre-syndrome.html Overview 1. Importance of vaccine safety 2. Vaccine side effects 3. Methods to evaluate vaccine safety 4. Pathogenesis of vaccine-induced sides effects + Some examples of hypothetical, unproven associations between vaccines en diseases ➔ vaccine criticism, vaccine hesitancy, vaccine refusal, anti-vaccine movement 62 Hypothetical, non-proven associations between vaccines and diseases Andre FE. Vaccine 2003; 21: 593-5 SARS-CoV-2 vaccine and alleged associations with health problems Female infertility Male infertility Overwhelmed or suppressed immune system Mutations in our DNA Health problems on the ‘long term’, e.g. cancer Vaccinee becomes an ‘infectious’ cloud of spike protein ….