Lecture 6: Influenza and RSV Vaccines PDF

Vaccines against Seasonal and Pandemic Influenza and Respiratory Syncytial Virus Amyn Malik, MBBS, MPH, PhD Assistant Professor  Table 1 Recommended Child and Adolescent Immunization Schedule for Ages 18 Years or Younger, United States, 2024...

Vaccines against Seasonal and Pandemic Influenza and Respiratory Syncytial Virus Amyn Malik, MBBS, MPH, PhD Assistant Professor  Table 1 Recommended Child and Adolescent Immunization Schedule for Ages 18 Years or Younger, United States, 2024 These recommendations must be read with the notes that follow. For those who fall behind or start late, provide catch-up vaccination at the earliest opportunity as indicated by the green bars. To determine minimum intervals between doses, see the catch-up schedule (Table 2). Vaccine and other immunizing agents Birth 1 mo 2 mos 4 mos 6 mos 9 mos 12 mos 15 mos 18 mos 19–23 mos 2–3 yrs 4–6 yrs 7–10 yrs 11–12 yrs 13–15 yrs 16 yrs 17–18 yrs Respiratory syncytial virus 1 dose depending on maternal 1 dose (8 through 19 months), See Notes (RSV-mAb [Nirsevimab]) RSV vaccination status, See Notes Hepatitis B (HepB) 1st dose ----- 2nd dose ----- ---------------------------- 3rd dose ---------------------------- Rotavirus (RV): RV1 (2-dose series), 1st dose 2nd dose See Notes RV5 (3-dose series) Diphtheria, tetanus, acellular pertussis 1st dose 2nd dose 3rd dose ----- 4th dose ------ 5th dose (DTaP 6 months in the US more recent 42 as clinical trials and knowledge more accumulated guideline changed  Influenza Vaccine Types Inactivated influenza vaccine (IIV) Since 1940s Administered by intramuscular injection Multidose vials contain thimerosal I singlevial multipledoses Some products contain residual egg protein Thimerosal may be used in some influenza vaccines as a preservative to prevent microbial growth 43  Influenza Vaccine Types Recombinant influenza vaccine (RIV) Recombinant hemagglutinin Administered by intramuscular injection Does not contain egg protein First approved for use in 2013 44  1 1948 Influenza Vaccine Types Live, attenuated influenza vaccine (LAIV) First approved for use in the United States in 2003 Administered intranasallyFused nasalspray as Grown in chicken eggs and contains residual egg protein Replicate effectively in the mucosa of the nasopharynx Vaccinated children can shed vaccine viruses in nasopharyngeal secretions for up to 3 weeks Transmission of shed LAIV viruses from vaccine recipients to unvaccinated persons has been documented but has not been reported to be associated with serious illness 45 it is live it canshedlive viruses Because transmission of flu notsure about sheddingbecause it hasn'tledto  Influenza Vaccine Types Trivalent vaccines A(H1N1), type A(H3N2), and type B 2strainsof type A I strainoftype Bcirculating Quadrivalent vaccines strain gocirculate have A(H1N1), type A(H3N2), and type B plus additional type B strain First introduced during the 2013–2014 season 46 give more than A strain injection we  Influenza Vaccines Vaccines are multivalent Vaccine-induced immunity tends to be crossimmunitymight be homotypic (strain-specific) present man proteinsitdifferent protein not n'eN aspecifictargeting Limited cross-subtype immunity strains circulating has multiple Especially important in immunologically naïve Young children – require two doses initially Pandemic – may require higher dose or adjuvant Incorporate each of the main human types/subtypes: A(H1N1), A(H3N2), Bs Either trivalent or quadrivalent 47 16  Influenza Vaccine Safety generallyprettysafe not really any adverse events but can belocal IIV inactive Soreness, redness, tenderness, or swelling at the injection site is common No clear link with GBS; risk would be no more than 1 to 2 cases per million RIV recombinant Tenderness: 48% Pain: 37% Headache: 20% Fatigue: 17% Muscle pain:13% LAIV liveattenuated Runny nose, nasal congestion (children) Sore throat, headache, tiredness/weakness, muscle aches, cough, chills, sinusitis (adults) 48  Vaccine production 49  Southern Hemisphere Breakdown Northern Hemisphere Breakdown Strain Selection: Happens from September to October, re ecting the u season differences in the Southern Hemisphere. Strain Selection: Takes place from February to March, based on surveillance data from the ongoing or just-ended u season. Reassortant Preparation: Starts from October to November, following strain selection. Reassortant Preparation: Occurs from March to April, creating reassortant viruses for vaccine production. SRID Reagent Preparation: Conducted from November to December, which is later than in the Northern Hemisphere. SRID Reagent Preparation: From April to May, reagents are prepared to ensure the antigen potency of the vaccine. Virus Seed Strain Production: Takes place between November and January. Virus Seed Strain Production: Happens between April and June to produce the virus seed strains needed for bulk production. Monovalent Bulk Production: Happens from December to February, following virus seed strain production. Monovalent Bulk Production: Takes place from May to July, where the bulk quantities of each selected strain are produced. TRI or Quadrivalent Blending: From January to March, different virus strains are combined into the nal vaccine TRI or Quadrivalent Blending: From June to August, different strains are combined to formulate the nal vaccine. formulation. Fill and Finish: Occurs between August and October, where the vaccine is packaged for distribution. Fill and Finish: Occurs between February and April, following blending and quality checks. Vaccine Release: From August to October, after quality control checks, the vaccine is approved for public release. Vaccine Release: From March to May, after regulatory approval. Submission of CMC Data: From August to October, the manufacturer submits data to regulatory bodies for nal approval. Submission of CMC Data: Happens from February to April, as part of the nal approval process. Clinical Trials: Conducted from April to September, ensuring safety and ef cacy before public distribution. Clinical Trials: Conducted between December and March, in alignment with vaccine production. Approval of Clinical Data: From July to September, regulatory authorities review the clinical trial data. Approval of Clinical Data: From March to April, ensuring the vaccine's safety and ef cacy before release. Vaccine Distribution: Begins around August to November, making the vaccine available for public use ahead of the u season. Vaccine Distribution: Begins around April to June, ensuring availability ahead of the Southern Hemisphere u season (April to September). adf.rkna.in licence b the Northern timeline for vaccine production differs theseregions w Hemisphere with southern eachstep adaptedto flu seasonin 50 to AprilMay Northern octoner Southern AprilMay September  Influenza Vaccines Because new strains of influenza appear frequently, the seasonal flu vaccine usually changes each year. Each season vaccine is generally designed to protect against three strains of influenza: two “A” strains, and one “B” strain. From start to finish—the selection of which three strains to target with the vaccine, to the production of the final product—the development process for the seasonal flu vaccine can take up to eight months. to develo yearly CDC, 2024 51  For 2024-2025 Egg-based vaccines an A/Victoria/4897/2022 (H1N1)pdm09-like virus; an A/Thailand/8/2022 (H3N2)-like virus; and (Updated) a B/Austria/1359417/2021 (B/Victoria lineage)-like virus. Cell- or recombinant-based vaccines an A/Wisconsin/67/2022 (H1N1)pdm09-like virus; an A/Massachusetts/18/2022 (H3N2)-like virus; and (Updated) a B/Austria/1359417/2021 (B/Victoria lineage)-like virus. 52 CDC, 2024 hemisphere canbedifferent vaccinefornorthernsouthern dependingonwhich circulationandsouthernJulyNorthernJanuary strain inhemisphere usessame vaccineduetolimited producersof vaccine also everycountry in that 53 Maufacturers available for vaccine by type available in us for current reason 54 CDC, 2024 overall in 50 60 coverage coveragevariesseasontoseasonslightly overall 7080 overall make certainagegroups but never reached in this population never reached 55 CDC, 2024 We are at suboptimal flu coverage  Influenza vaccine effectiveness 56 57 coverages we have not at about 80 coverage even in  Benefits of flu vaccination Adults age 65 years represented a majority of the averted deaths (80%) and hospitalizations (58%). Children age 6 months to 17 years represented 43% of averted symptomatic illness and 51% of averted medical visits. 58 vaccine benefits extend to children adults flu regardless of age  Influenza Vaccines Influenza vaccine effectiveness Antigenic match to Populations (e.g., age, Outcome used to Season Viral subtype circulating strains underlying diseases) estimate effectiveness V.LY e children adults typeAtypeB 59  a.EE ifne 60 Yildirim et al Clinical Infectious Diseases 2021;73(10):1759–67 https://doi.org/10.1093/cid/ciab709 wide variations seasonary boxedvaluesforvac can be due to match it strainchangesbetweenselected whenvaccinegiven cangetrangedof effectiveness goodmatchshows vaccine highly effective Won't be gettingrange of numbers  Vaccine Effectiveness Against Pediatric InfluenzaA–Associated Urgent Care, Emergency Department, and Hospital Encounters During the 2022–2023 Season 61 K adams et al. Clinical Infectious diseases, 2024 depending on age groups effectiveness different in terms of vaccineeffectivenessbasedonbox some variation for one season  62 Belongia et al, Lancet Infect Dis 2016 depending on agegroup Pediatrics us adults varied for vaccineeffectiveness for different type be different reasons for vaccine effectiveness mayne strain type could H3N2 63 Belongia et al, Lancet Infect Dis 2016 different estimates for vaccine effectiveness VE for type B 64 different estimates for vaccine effectiveness Estimates of 2023–24 Seasonal Influenza Vaccine Effectiveness Frutos AM, Price AM, Harker E, et al. Interim Estimates of 2023–24 Seasonal Influenza Vaccine 65 Effectiveness — United States. MMWR Morb Mortal Wkly Rep 2024;73:168–174. DOI: http://dx.doi.org/10.15585/mmwr.mm7308a3. 50 mark for vaccine effectiveness At About 33 49 between importance stilldebated Original antigenic sin occurs when the immune system first encounters virus **A** and creates antibodies specific to it. In future exposures to related but slightly different viruses, like **A'** or **A''**, the immune system preferentially produces antibodies against the original **A** virus, rather than developing new antibodies tailored to **A'** or **A''**. This can lead to a less effective immune response to the newer variants. Original Antigenic Sin: How First Exposure Shapes Lifelong Anti–Influenza Virus Immune Responses body keeps going back to original strain 66 Zhagng J Immunol 2019:202 (2) 335-340; DOI: https://doi.org/10.4049/jimmunol.1801149 encounters antigen producesantibodies high level first time body different still responds like to originalvirus antibody not high you encounter virus slightly next time imithb itsoriginal strain andprodaleantibodies to originalstrainwhich from practical strain different ks t.fi protected protection ofantibodies effective andmaynotbecompletely canlead to not  RSV 67 up icoming Respiratory Syncytial Virus (RSV) Isolated in the 1950s in animal introduced models shortlywheninfluenzavaccine First identified in humans in infants with severe LRTI Single-stranded RNA virus getting forlongtimebutnowjust 144 HYLIyyen 68 Respiratory Syncytial Virus (RSV) has many protein on surface G protein on the viral envelop attaches to host cell attachment F protein causes fusion and cell entry (vaccine target) in kind Mostly conserved across strains ASB 2 antigenic subtypes (A and B) – tend to co-circulate Can accumulate antigenic drift No rapid antigenic shift F conserved across 2subtypes in evolution Typically circulates in November- March in North America 69  Clinical Manifestations in at-risk groups Infants Upper respiratory tract infection Acute Otitis Media Bronchiolitis 1-3% of children are hospitalized for RSV bronchiolitis Older adults Severe LRTI Wheezing, bronchitis, pneumonia Immunocompromised or underlying cardiorespiratory illness Asthma, COPD, congestive heart failure exacerbation High risk for severe LRTI 70  Immunity? Typically lasts only one season – waning antibodies seasonal epidemics May be due to antigenic drifts, no antigenic shift Reinfection well established in subsequent seasons Children < 2 capable of recurrent symptomatic infections Co-infections with other viruses and bacteria are common different immunological triggers pathways 71  Transmission Spreads by respiratory droplet Direct person-person contact-with saliva, mucus or nasal discharge Unclean hands (can survive 30 min or more) Unclean surfaces (can survive up to 6 hours) fomite important for transmission 72  Epidemiology 68% of infants are infected in the first year of life and 97% by age 2 years very common in young children 2.1 million outpatient (non- hospitalization) visits among children younger than 5 years old 58,000-80,000 hospitalizations among children younger than 5 years old 100,000-160,000 hospitalizations among adults 60 years and older 73 CDC, 2024; CDC Webinar, 2023 Rsv poses lots of burden on health system RSV Hospitalizations by Age March seasonalOctober to Oto 4 or 654older beingmostly affected 74 CDC, 2024 75 CDC, 2024 Stats 76 very young Children are at highest rilk of hospitalization  77 uncertainty withestimates  Seasonality of RSV Hospitalizations in Children ( 60 years conserved all target of protein area f Moderna mResvia- mRNA – nucleoside coding glycoprotein F (RSV A) Pfizer Abrysvo – Protein subunit -recombinant RSV F protein antigen (RSV A) GSK Arexvy – Protein subunit - recombinant RSV F protein antigen (RSV A and B)quivalent from approved byFDA 28Ehffif.hn all licensed in usand 79 CDC, 2024; alltarget the Fprotein  Approved RSV Vaccines 912m nms Effectiveness* Effectiveness* Efficacyⱡ ER encounters: 79% ER encounters: 77% Sx at 4mo: 80% cromolinical trials Hospitalization: 73% Hospitalization: 83% Sx at 12mo: 56% *Real world effectiveness ⱡ Phase 2/3 randomized blind placebo clinical trial 80 CDC, 2024 Comparing Pfizer and GSK Vaccine Effectiveness motor father 1styearof vulcine 2nd yr of Valline 1styearof vulcine 2nd yr of Valline 81 of waning immunity shows indication  Moderna Vaccine Effectiveness against symptomatic RSV 82 Wilson, E et al. 2023 MRNAvaccine has b w 82 Depending on how you describe RSU Greater than 2 or 3 Symptoms 8U vaccine effectiveness  CDC Vaccine recommendations RSV vaccine recommended for all adults 75 and older and adults 60- 75 at increased risk Single dose only (not currently recommended for seasonal vaccination) This was revised in August, 2024. Before that CDC was recommending all adults 60+ Pregnant women between 32-36 weeks (prevent RSV in infants < 6mo) – CDC only recommends Pfizer Abrysvo enough to transfer antibodies to placenta for fetus 83 CDC, 2024;  Adverse Effects from mRNA Vaccine Severe Reactogenicity Moderna 84 MMWR, Aug 15 2024 higherlikelihood of reactogenicity but no other serious adverse events reported Adverse Effects from Protein Subunit Vaccines GSK and Pfizer awite sate Based on data from one season: Guillain-Barre Syndrome some increased like loud but CI are quite Adjusted incidence rate ratio (risk vs Wade control) GSK - 2.30 (95% CI = 0.39–13.72) Pfizer - 4.48 (95% CI = 0.88– 22.90) *based on medical claims data Immune Thrombocytopenia GSK – no confirmed risk 85 MMWR, Aug 15 2024 surveillance is ongoing have only one year of vaccine  Thanks! 86