Influenza. Alan P. Agins, Ph.D Objectives. Influenza Update: Influenza. Disclosures. Influenza Virus.

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1 Influenza Update: 2016 Alan P. Agins, Ph.D. President: PRN Associates, Ltd Continuing Medical Education Tucson, AZ Objectives Understand how antigenic drift and antigenic shift are related to epidemics, pandemics and vaccine effectiveness) Compare and contrast the various influenza vaccine options Discuss the most recent ACIP guidelines for influenza vaccination Describe the basic and clinical pharmacology of drugs used to prevent or treat influenza Educate patients with respect to the issues of mercury, egg allergy and other concerns regarding the flu vaccine Disclosures The speaker has no financial or other conflicts of interest to disclose Influenza Orthomyxoviruses Pleomorphic Three types - A,B,C Febrile, respiratory illness with systemic symptoms Credits: CDC Influenza Virus CDC/ Douglas Jordan Flu virus is roughly round can also be elongated or irregularly shaped Eight segments of singlestrand RNA genetic instructions for making new copies of virus Most striking feature is a layer of spikes projecting from its surface Influenza: Surface Proteins CDC/ Douglas Jordan Hemagglutinin Trimeric Protein 500 copies per virion Matrix 2 (M2) Tetrameric Protein 10 copies per virion Neuraminidase Tetrameric Protein 100 copies per virion Alan P. Agins, Ph.D

2 Clinically Relevant Influenza Viruses Type A Type B Type C Potentially severe illness Rapidly changing Epidemics and Pandemics Humans (all ages) and animals (pigs, horses, seals, whales) Usually less severe illness More stable/uniform Epidemics only Humans only Primarily children/elders in facilities Usually mild or asymptomatic illness Minimal public health impact Type A Influenza 16 different hemagglutinins (HA) 9 different neuraminidases (NA) Human disease historically caused by: three subtypes of HA (H1, H2, H3) two subtypes of NA (N1 and N2) All known subtypes of influenza A can be found in birds, but only subtypes H5 and H7 have caused severe outbreaks of disease in birds Pigs and Horses are also resevoirs for a few HAs and NAs Naming of Flu Viruses Influenza Infection A / California / 7 / 2009 (H1N1) pdm09-like virus Wikimedia Commons Source: User:YK Times ( Transmission Airborne droplets that come from coughs and sneezes Touching objects contaminated with particles from an infected person s nose and throat. Illness Incubation period: 1 to 4 days (~ 2 days) Illness typically resolves after 3 to 7 days for the majority of persons, although cough and malaise can persist for over 2 weeks. Influenza Viral Replication / Shedding Peak transmission Fever And Symptoms 24h 48h 72h 96h 5d 6d 7d 8d 9d 10d Alan P. Agins, Ph.D

3 Influenza Transmission /Contagiousness Adults can be contagious from 1 day before symptoms begin to 5-7 days (or more- see below) after symptoms start Young children can shed virus for several days before their illness onset and be contagious for more than 10 days after onset of symptoms. Severely immunocompromised persons can shed virus for weeks or months. How long does the flu virus survive on surfaces? Only minutes on bare hands Enough time for transfer to mouth, nose, eyes. Flu virus can survive for hours on other surfaces One study showed flu virus can live up to: 48 hours on hard, nonporous surfaces (stainless steel) 12 hours on cloth and tissues. Influenza Complications Primary influenza viral pneumonia Secondary bacterial infection Streptococcus pneumoniae Staphlyococcus aureus Hemophilus influenzae Croup (young children) Pneumonia & Influenza 8 th leading cause of death Major causes of flu-associated death Bacterial pneumonia Cardiac failure / MI Historically, 90% of deaths in > 65 yrs Protection against infection or re-infection The Usual (and it does works) Handwashing, avoiding direct contact with infected, avoid surfaces that may be contaminated with the flu virus Alcohol-based gel or foam hand sanitizers Natural Immunity IgG and IgA IgG less efficient but lasts longer Antibodies to both HA and NA important antibody to HA more important (can neutralize) Vaccines Immunity and Vaccine Issues (Reason for Epidemics) Influenza virus is one of the most changeable of viruses Antigenic Drift RNA Small, continuous changes occur in both type A and B during replication (mutations) Process alled antigenic drift Drifting is frequent enough to make the new strain of virus often unrecognizable to the human immune system Need for new vaccine annually Alan P. Agins, Ph.D

4 Immunity and Vaccine Issues (Reason for Pandemics) Type A influenza (only) undergoes infrequent and sudden changes, called antigenic shift Occurs when two different flu strains infect the same cell and exchange genetic material can occur in birds or swine The novel assortment of HA or NA proteins in a shifted virus creates a new influenza A subtype Antigenic Shift H1N1pdm09 H1N1 A/California/2009 (H1N1) quadruple reassortant virus Vaccination > 100 influenza centers in >100 countries conduct year-round surveillance for influenza viruses and disease activity. Send influenza viruses for additional analyses to the five WHO Collaborating Centers for Reference and Research on Influenza: Atlanta, Georgia, (CDC) London, UK (National Institute for Medical Research) Melbourne, Australia (Victoria Infectious Diseases Reference Laboratory) Tokyo, Japan (National Institute for Infectious Diseases) Beijing, China (National Institute for Viral Disease Control and Prevention). Vaccine Development surveillance select strains prepare reassortants standardize antigen assign potency review/license formulate/test/package vaccinate licensed influenza vaccines All will have: A/California/7/2009 (H1N1)pdm09-like virus, A/Hong Kong/4801/2014 (H3N2)-like virus B/Brisbane/60/2008-like virus (B/Victoria lineage) Quadrivalent influenza vaccines will also contain B/Phuket/3073/2013-like virus (B/Yamagata lineage). This represents a change in the influenza A(H3N2) component and a change in the influenza B lineage included in the trivalent vaccine compared with the composition of the influenza vaccines. Alan P. Agins, Ph.D

5 How Effective is the Flu Vaccine? Recent studies show vaccine can reduce the risk of flu illness by about 50-60% among the overall population during seasons when most circulating flu viruses are like the viruses the flu vaccine is designed to protect against. How effective is the flu vaccine Efficacy (prevention in controlled trials) Effectiveness (prevention of illness in vaccinated populations) Depend on: Age and immunocompetence of the vaccine recipient Flu vaccine works best among young, healthy adults and older children; Lesser benefit in studies of young children (e.g., those younger than2 years of age) and older adults Degree of similarity between the viruses in the vaccine and those in circulation Outcome being measured repeated finding in studies is that vaccination produces a greater reduction in serologicallyconfirmed influenza than in clinical influenza (ie., ILI). Does Vaccine always match the virus? When there s a mismatch Since 1990, there has only been one season ( ) when there was very low cross-reaction and four seasons ( , , & ) when there was low cross-reaction vaccine was ineffective (VE~23%) against the predominant H3N2 A strain that was circulating H3N2 strains associated with moribity & mortality Rate of flu-related hospitalizations among pts > 65 years was the highest recorded in the 10 years since the CDC began tracking that measure. H3N2 strain also hit children hard with 145 labconfirmed pediatric influenza deaths, which is likely an underestimate Flu vaccination benefits 2014 study showed that flu vaccine reduced children s risk of flu-related pediatric intensive care unit (PICU) admission by 74% during flu seasons from study showed that flu vaccination was associated with a 71% reduction in flu-related hospitalizations among adults of all ages and a 77% reduction among adults 50 years of age and older during the flu season Studies from 2008, 2011 & 2013 reported vaccination associated with lower rates of some cardiac events among people with heart disease, especially those who had had a cardiac event in the past year Flu vaccination benefits Flu vaccination also has been shown to be associated with reduced (79%) hospitalizations among people with diabetes (1997) and chronic lung disease (52%) 2010 study showed that giving flu vaccine to pregnant women was 92% effective in preventing hospitalization of infants for flu for up to 6 months after birth 2011 reviewing flu vaccine effectiveness over the course of three flu seasons estimated that vaccination lowered the risk of hospitalizations by 61% in people 50 years of age and older Alan P. Agins, Ph.D

6 Rates of vaccination among Healthcare Workers Coverage in Pharmacists 95% Physicians and nurses 89% NPs and PAs 87% Assistants and aides 64% Required to be vaccinated by employer 96% Not required but offered on-site (multiple times) at no cost 74%-84% Vaccination not required, promoted, or offered on site 44% Influenza Vaccines IIV4 - Standard Dose Fluarix * Quadrivalent (Q) FluLaval (Q) Fluzone (Q) IIV3 - Standard Dose Afluria, Fluarix, FluLaval, Fluvirin, Fluzone, Fluzone Intradermal cciiv3(cell-culture) Flucelvax RIV3 - Recombinant Influenza Vaccine FluBlok IIV3 - High Dose Fluzone High Dose LAIV4 - FluMist Quadrivalent * PharmaJet Stratis 0.5ml Needle-free Jet Injector ACIP votes that LAIV should not be used during the flu season Action based on data showing poor or relatively lower effectiveness of LAIV from 2013 through LAIV among children 2 years through 17 years during season against any flu virus was 3 percent In comparison, IIV (flu shots) had a VE estimate of 63 percent against any flu virus among children 2 years through 17 years. New for 2016 Adjuvant Flu Vaccine approved FLUAD was licensed in November 2015 as the first adjuvanted seasonal flu vaccine marketed in the United States. Approved under an accelerated review process Will be available during flu season Approved for > 65 yrs of age Trivalent vaccine contains MF59 adjuvant, an oil-in-water emulsion of squalene oil. No randomized studies comparing FLUAD with Fluzone High-Dose vaccine. Timing of Vaccination Vaccination optimally should occur before onset of influenza activity in the community. HCPs should offer vaccination soon after vaccine becomes available (by October, if possible). Vaccination should be offered as long as influenza viruses are circulating. Children aged 6 months through 8 years who require 2 doses should receive their first dose as soon as possible after vaccine becomes available, and the second dose 4 weeks later. To avoid missed opportunities for vaccination, providers should offer vaccination during routine health care visits and hospitalizations when vaccine is available. Herd Immunity Is 100% efficacy necessary? The objectives of vaccination coverage proposed in the United States 80% in healthy persons and 90% in highrisk persons are sufficient to establish herd immunity, Alan P. Agins, Ph.D

7 Timing of Vaccine for Elderly? 2010 study noted a statistically significant decline in titers 6 months post-vaccination among persons aged 65 years although titers still met European Medicines Agency levels considered adequate for protection Delaying vaccination might permit greater immunity later in the season.... However Deferral might result in missed opportunities to vaccinate and difficulties in vaccinating a population within a limited time Time of Day for Vaccine Recent Study (published in Vaccine - April 2016) examined flu vaccine administrations in 276 adult patients aged 65 years or older to determine whether the immunization would be more effective at a specific time of day Pt vaccinated between 9 AM and 11 AM (morning session) vs between 3 PM and 5 PM (afternoon session) Pts vaccinated in AM had better significantly larger Ab response for the H1N1 A- and B-strains compared to PM patients. For the H3N2 A-strain, there seemed to be no significant differences between AM and PM patients Influenza vaccine dosing algorithm for children aged 6 months through 8 years Inactivated Influenza Vaccine Side Effects Most frequent (children & adults) Pain and other injection-site reactions Up to 64% of people vaccinated with TIV experience pain at the injection site, which usually resolves in <2 days without treatment Fever, malaise, myalgia, and other systemic symptoms that can occur after vaccination with TIV most often affect persons who have had no previous exposure to the influenza virus antigens in the vaccine (e.g., young children). Contraindications and Precautions to the Use of Influenza Vaccines IIV (includes IIV3, II4, and cciiv) Contraindications: Severe allergic reaction to any component of the vaccine, including egg protein, or after previous dose of any influenza vaccine. Precautions: Moderate to severe illness with or without fever; history of Guillain-Barré syndrome within 6 weeks of receipt of influenza vaccine. RIV History of severe allergic reaction to any component of the vaccine (no egg issues). Invalid Contraindications for Vaccination Minor illness Hx of mild-moderate local reaction or fever Antimicrobial therapy Disease exposure or convalescence Pregnant or immunosuppressed person in the household (refer to individual vaccine information) Premature birth Breastfeeding Allergies to products not in vaccine Alan P. Agins, Ph.D

8 Recommendations regarding influenza vaccination for persons who report allergy to eggs Acetaminophen and Flu Vaccine Study reported reduced antibody response following vaccine in children using prophylactic acetaminophen Low grade fever is part of normal inflammatory / immune response. Slightly elevated body temperature may enhance immune cell activation/division/ antibody production Recommendations Do not routinely pretreat children with acetaminophen prior to vaccine (any vaccine) Reserve for post-vaccination significant fever, or if child is at risk for fever and febrile seizures. Viral Targets for drugs Hemagglutinin (H) Neuraminidase (N) oseltamivir zanamivir peramivir M2 Protein amantadine rimantadine Adamantanes Amantadine, Rimantadine Mechanism of action Interfere with M2 ion channel of influenza A viruses Interfere with virus assembly during replication of influenza A viruses Decrease the release of influenza A viral particles into the host cell Decrease influenza A viral shedding No activity against influenza B viruses Amantadine, Rimantadine Antiviral Drug Resistance: Role of Neuraminidase In recent past seasons, there continues to be high levels of resistance (> 99%) to adamantanes among influenza A (H3N2) and influenza A (H1N1) pdm09 ("2009 H1N1") viruses. Therefore, amantadine and rimantadine are not recommended for antiviral treatment or chemoprophylaxis of currently circulating influenza A viruses. Sialic acid Sialic acid Sources: NIH and A.Agins Sialic acid Alan P. Agins, Ph.D

9 Neuraminidase Inhibitors Zanamivir and Oseltamivir Neuraminidase Inhibitors Prevent the NA proteins on viral surface from breaking sialic acid HA coupling. Viral budding and downstream replication are inhibited. Sialic acid Sialic acid Emerging viruses stick to the cell membrane or other viruses Summary of Influenza Antiviral Treatment Recommendations Clinical trials and observational data show that early antiviral treatment can shorten duration of fever and illness symptoms, and may reduce the risk of complications (e.g., otitis media in young children, pneumonia, and respiratory failure). Early treatment of hospitalized patients can reduce death. In hospitalized children, early antiviral treatment has been shown to shorten the duration of hospitalization. Summary of Influenza Antiviral Treatment Recommendations Clinical benefit is greatest when antiviral treatment is administered early, especially within 48 hours of influenza illness onset. Antiviral treatment is recommended as early as possible for any patient with confirmed or suspected influenza who: is hospitalized; has severe, complicated, or progressive illness; or is at higher risk for influenza complications. Persons at higher risk for influenza complications recommended for antiviral treatment include: Children < 2 years: Adults > 65 years Persons with: chronic pulmonary (including asthma) CV (except HTN alone) Renal, Hepatic disease Hematological (including sickle cell disease) Metabolic disorders (including DM) Neurologic and neurodevelopment conditions (including disorders of the brain, spinal cord, peripheral nerve, and muscle, such as cerebral palsy, epilepsy [seizure disorders], stroke, intellectual disability [mental retardation], moderate to severe developmental delay, muscular dystrophy, or spinal cord injury); Persons at higher risk for influenza complications recommended for antiviral treatment include: Persons with immunosuppression, including that caused by medications or by HIV infection Women who are pregnant or postpartum (within 2 weeks after delivery) Persons aged younger than 19 years who are receiving long-term aspirin therapy American Indians/Alaska Natives Persons who are morbidly obese (i.e., body mass index is equal to or greater than 40); and Residents of nursing homes and other chronic care facilities. Alan P. Agins, Ph.D

10 Duration of Treatment or Chemoprophylaxis Antiviral Chemoprophylaxis Annual vaccination best way to prevent influenza Antivirals - 70% to 90% effective in preventing influenza and are useful adjuncts to vaccination CDC does not recommend widespread or routine chemoprophylaxis to limit possibilities for resistance Emphasis on early treatment and monitoring is an alternative to chemoprophylaxis after a suspected exposure for some persons Thanks for listening.... Stay healthy this season Alan Alan P. Agins, Ph.D