Determining How Well a Vaccine Works -- Vaccine Match and Host Factors

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1 Key Pints Hw Well D Influenza (Flu) Vaccines Wrk? General There are tw types f flu vaccines: Trivalent inactivated vaccines ( flu shts ), which are given with a needle and cntain inactivated (killed) virus that cannt cause influenza virus infectin; and a live attenuated influenza vaccine ( nasal spray flu vaccine ), which is sprayed int the nse and cntains attenuated (weakened) virus (smetimes called LAIV). Influenza vaccines prtect against infectin and illness caused by influenza viruses. Flu vaccines will NOT prtect against infectin and illness caused by ther viruses that can als cause influenza-like symptms. There are many ther viruses besides influenza that can result in influenza-like illness (ILI) that spread during the flu seasn. Researchers try t tell hw well a vaccine wrks in rder t cntinually assess and cnfirm the value f influenza vaccines as a public health interventin. Study results abut hw well a flu vaccine wrks can vary based n study design, utcme(s) measured, ppulatin studied and the seasn in which the vaccine was studied. These differences can make it difficult t cmpare ne study s results with anther s. Hw well the flu vaccine wrks (r its ability t prevent influenza illness) can range widely frm seasn t seasn and als can vary depending n wh is being vaccinated. While determining hw well a flu vaccine wrks is challenging, in general, recent studies have supprted the cnclusin that influenza vaccinatin benefits public health, especially when the viruses in the vaccine and circulating viruses are well-matched. (See Current Effrts t Study Hw Well Influenza Vaccines Wrk. ) Determining Hw Well a Vaccine Wrks -- Vaccine Match and Hst Factrs Tw factrs play an imprtant rle in determining the likelihd that influenza vaccine will prtect a persn frm influenza illness: 1) characteristics f the persn being vaccinated (such as their age and health), and 2) the similarity r "match" between the influenza viruses in the vaccine and thse spreading in the cmmunity. In general, the flu vaccine wrks best amng yung healthy adults and lder children. Lesser effects f flu vaccine are ften fund in studies f yung children (e.g., thse yunger than 2 years f age) and lder adults. Older peple with weaker immune systems ften have a lwer prtective immune respnse after influenza vaccinatin cmpared t yunger, healthier Prepared by Influenza Divisin Page 1 f 7

2 Key Pints Hw Well D Influenza (Flu) Vaccines Wrk? persns. This can result in lwer levels f vaccine effectiveness in these peple. The ther factr affecting hw well the flu vaccine wrks is the match between the influenza viruses cntained in the vaccine and thse spreading in the cmmunity. The clser the match, the better the vaccine is likely t be in preventing influenza illness. If the viruses in the vaccine are very different frm circulating influenza viruses, vaccine effects can be lwer. Influenza viruses are cnstantly changing they can change frm ne seasn t the next r they can even change within the curse f the same seasn. Each year, experts must select the viruses t include in the influenza vaccine many mnths in advance f the influenza seasn in rder fr vaccine t be prduced and delivered n time. Because f the lng lead time in selecting the viruses t be included in the vaccine and the fact that influenza viruses are cnstantly changing, selecting the right influenza viruses t include in the vaccine is a challenging task. When cmbined, match and hst factrs mean that it is unlikely that any influenza vaccine will ever be 100% effective. During years when the viruses in the vaccine and circulating viruses are nt well matched, it s pssible that n benefit frm vaccinatin may be bserved. During years when the viruses in the vaccine and circulating viruses are very well matched, it s pssible t measure substantial benefits frm vaccinatin in terms f preventing influenza illness. Hwever, even during years when the vaccine match is very gd, the benefits f vaccinatin will vary acrss the ppulatin, depending n hst factrs like the health and age f the persn being vaccinated and even ptentially which vaccine was used. Fr infrmatin abut recent studies evaluating hw well flu vaccine wrks, see Current Effrts t Study Hw Well Influenza Vaccines Wrk. Ways t Measure Hw Well Vaccines Wrk -- Study Methds Hw well a vaccine wrks can be measured thrugh different kinds f studies. Randmized studies, in which peple are randmly assigned t receive either vaccine r placeb (e.g., saline slutin), and then fllwed t see hw many in each grup get influenza, are the gld standard (best methd) fr determining hw well a vaccine wrks. The measurement f vaccine effect frm a randmized (placeb-cntrlled) study is referred t as efficacy. Prepared by Influenza Divisin Page 2 f 7

3 Key Pints Hw Well D Influenza (Flu) Vaccines Wrk? Observatinal studies are studies in which subjects wh chse t be vaccinated are cmpared t thse wh chse nt t be vaccinated. This means that vaccinatin f study subjects is nt randmized. The measurement f vaccine effect frm an bservatinal study is referred t as effectiveness. Randmized studies are difficult t cnduct and particularly undesirable in high-risk grups, where withhlding vaccine frm peple recmmended fr vaccinatin wuld place them at risk fr infectin, illness and pssibly serius cmplicatins. Fr that reasn, mst recent studies t measure hw well flu vaccine wrks have been bservatinal studies. Many bservatinal studies use a case-cntrl design, in which cases f influenza illness are cmpared with a grup f peple (cntrl grup) wh did nt get influenza. One aspect f the design f bservatinal studies that can influence results is the chice f the cntrl (cmparisn) grup. The cntrl grup can include peple wh did nt have influenza, r wh have n recrd f seeking care fr influenza symptms. In sme studies, the cntrl grup may cnsist f peple wh had respiratry symptms fr which they sught medical care, but wh tested negative fr influenza. When study cntrls differ in unmeasurable ways frm cases, that may intrduce biases that can increase r decrease estimates f hw well the vaccine wrked. Fr that reasn, members f the cntrl grup wh dn t have influenza shuld ideally be similar t study subjects with influenza. Generally speaking, cases shuld cme frm the same ppulatin as cntrls. In additin, it can be difficult t directly cmpare results between studies that used different cmparisn grups. Even if bth studies were well-cnducted, ne wuld expect the results t be different because the chice f the cmparisn grup in nn-randmized studies can influence the estimate f the vaccine s effect. Other factrs that can affect results are the numbers f cases (peple wh develped flu illness) in the study and the number f peple eligible fr, r enrlled in a study (again, smaller numbers can make results less reliable.) Therefre, when assessing hw well a vaccine wrks, it is imprtant t cnsider estimates derived frm multiple studies, using different study designs. Ways t Measure Hw Well Vaccines Wrk -- Outcme Measured Prepared by Influenza Divisin Page 3 f 7

4 Key Pints Hw Well D Influenza (Flu) Vaccines Wrk? Studies als can assess hw well a vaccine wrks at preventing different utcmes. Fr example, the utcmes can be mre brad, like measuring influenza-like illness* (which includes illness caused by ther viruses in additin t flu viruses), r they can be mre specific t flu, like measuring labratrycnfirmed influenza virus infectin. The use f labratry-cnfirmed influenza cases is likely t yield mre accurate estimates cmpared t studies that use nn-specific case definitins (such as influenza-like illness). Generally, the lwest estimates f flu vaccine effectiveness are fund in studies using nn-influenza specific, nn-labratry-cnfirmed utcmes, such as studies using all deaths r all respiratry illnesses r all respiratryrelated hspitalizatins. Higher (and mre accurate) estimates are usually fund in studies in which the utcme is labratry-cnfirmed influenza. Influenza infectin can be cnfirmed in the labratry by using a variety f tests, including using reverse transcriptase plymerase chain reactin (RT-PCR), rapid influenza diagnstic tests, immunflurescence, viral culture and serlgy (which is measuring the presence and level f influenza antibdies in smene s bld). Viral culture and RT-PCR testing are likely t prvide mre accurate results. The sle use f serlgy t diagnse influenza infectin may result in an verestimatin f vaccine benefit. This happens because peple with pre-existing influenza antibdies frm prir infectins r vaccinatins may nt make mre antibdies if they becme infected with influenza. A study by Bridges et al (JAMA 2000) cnducted amng healthy adults illustrates hw the utcme measured can impact estimates f hw well a vaccine wrks. The results frm this study shwed that the inactivated influenza vaccine was 86% efficacius against labratry-cnfirmed influenza, but nly 10% efficacius against all respiratry illnesses in the same ppulatin and year. Current Effrts t Study Hw Well Influenza Vaccines Wrk Scientists cntinue t wrk n better ways t design, cnduct and evaluate nn-randmized (i.e., bservatinal) studies t assess hw well flu vaccines wrk. Prepared by Influenza Divisin Page 4 f 7

5 Key Pints Hw Well D Influenza (Flu) Vaccines Wrk? CDC has been wrking with researchers at universities and hspitals since the influenza seasn t estimate hw well influenza vaccine wrks thrugh bservatinal studies using labratrycnfirmed influenza as the utcme. These studies currently use RT-PCR cnfirmed medically-attended influenza virus infectins as a specific utcme. CDC s studies are cnducted in five sites acrss the United States t gather mre representative data. T assess hw well the vaccine wrks acrss different age grups, CDC s studies f vaccine effects include all peple aged 6 mnths and lder recmmended fr an annual influenza vaccinatin. Similar studies are being dne in Australia, Canada and Eurpe. Preliminary data fr the influenza seasn indicate that influenza vaccine effectiveness was abut 60% acrss all age grups, and that almst all influenza viruses islated frm study participants were well-matched t the vaccine strains. (Unpublished CDC data) A randmized study by Mnt et al lking at the influenza seasn fund trivalent inactivated vaccine (flu sht) prtected 7 ut f 10 peple frm influenza illness. The results f studies lking at hw well LAIV wrks range in the same way and fr the same reasns that study results f hw well the flu sht wrks have ranged. The main study that led t the licensure f LAIV was ne cnducted in children that shwed that LAIV prtected up t 9 ut f 10 children vaccinated frm getting sick with the flu. A recent meta-analysis f randmized clinical trials f LAIV in children fund that 2 dses f LAIV in vaccine-naïve children prevented infectin with 77% f antigenically similar viruses and 72% f all strains regardless f antigenic similarity. The substantial burden f influenza-assciated illness and death in the United States cmbined with the verall evidence frm a variety f studies shwing that influenza vaccines d ffer prtectin against influenza illness supprt the current U.S. influenza vaccinatin recmmendatins. It s imprtant t nte, hwever, that hw well flu vaccines wrk t prtect against flu illness will cntinue t vary each year, depending especially n the match between influenza viruses used t make vaccine and the influenza Prepared by Influenza Divisin Page 5 f 7

6 Key Pints Hw Well D Influenza (Flu) Vaccines Wrk? viruses that are spreading and causing illness in the cmmunity as well as the characteristics f the persn being vaccinated. Fr mre infrmatin abut studies measuring hw well vaccines wrk, see the references belw. *Influenza-like illness (ILI) is defined as fever (temperature f 100 F [37.8 C] r greater) and a cugh and/r a sre thrat. References Ashkenazi S, Vertruyen A, Arístegui J, Espsit S, McKeith DD, Klemla T, Bilek J, Kühr J, Bujnwski T, Desgrandchamps D, Cheng SM, Skinner J, Gruber WC, Frrest BD; CAIV-T Study Grup. Superir relative efficacy f live attenuated influenza vaccine cmpared with inactivated influenza vaccine in yung children with recurrent respiratry tract infectins. Pediatr Infect Dis J. 2006;25(10): (PDF link) Belshe RB, Mendelman PM, Treanr J, King J, Gruber WC, Piedra P, Bernstein DI, Hayden FG, Ktlff K, Zangwill K, Iacuzi D, Wlff M. The efficacy f live attenuated, cld-adapted, trivalent, intranasal influenza virus vaccine in children. N Engl J Med. 1998;338(20): (PDF link) Belshe RB, Gruber WC. Preventin f titis media in children with live attenuated influenza vaccine given intranasally. Pediatr Infect Dis J. 2000;19(5 Suppl):S Belshe RB, Edwards KM, Vesikari T, Black SV, Walker RE, Hultquist M, Kemble G, Cnnr EM; CAIV-T Cmparative Efficacy Study Grup. Live attenuated versus inactivated influenza vaccine in infants and yung children. N Engl J Med. 2007;356(7): (PDF link) Beran J, Vesikari T, Wertzva V, Karvnen A, Hnegr K, Lindblad N, Van Belle P, Peeters M, Innis BL, Devaster JM. Efficacy f inactivated split-virus influenza vaccine against culture-cnfirmed influenza in healthy adults: a prspective, randmized, placeb-cntrlled trial. J Infect Dis 2009;200(12): (PDF link) Bridges CB, Thmpsn WW, Meltzer MI, Reeve GR, Talamnti WJ, Cx NJ, Lilac HA, Hall H, Klimv A, Fukuda K. Effectiveness and cst-benefit f influenza vaccinatin f healthy wrking adults: A randmized cntrlled trial. JAMA. 2000;284(13): (PDF link) Fleming DM, Crvari P, Wahn U, Klemla T, Schlesinger Y, Langussis A, Øymar K, Garcia ML, Krygier A, Csta H, Heininger U, Pregaldien JL, Cheng SM, Skinner J, Razmpur A, Saville M, Gruber WC, Frrest B; CAIV-T Asthma Study Grup. Cmparisn f the efficacy and safety f live attenuated cld- Prepared by Influenza Divisin Page 6 f 7

7 Key Pints Hw Well D Influenza (Flu) Vaccines Wrk? adapted influenza vaccine, trivalent, with trivalent inactivated influenza virus vaccine in children and adlescents with asthma. Pediatr Infect Dis J. 2006;25(10): Gvaert TM, Thijs CT, Masurel N, Sprenger MJ, Dinant GJ, Knttnerus JA. The efficacy f influenza vaccinatin in elderly individuals. A randmized dubleblind placeb-cntrlled trial. JAMA. 1994;272(21): (PDF link) Herrera GA, Iwane MK, Crtese M, Brwn C, Gershman K, Shupe A, Averhff F, Chaves SS, Gargiull P, Bridges CB. Influenza vaccine effectiveness amng year-ld persns during a seasn f pr antigenic match between vaccine and circulating influenza virus strains: Clrad, United States, Vaccine. 2007;25(1): (PDF link) Hayward AC, Harling R, Wetten S, Jhnsn A, Munr S, Smedley J, Murad S, Watsn JM; Effectiveness f an influenza vaccine prgramme fr care hme staff t prevent death, mrbidity, and health service use amng residents: cluster randmized cntrlled trial. BMJ 2006;333:1241. (PDF link) Hberman A, Greenberg DP, Paradise JL, Rckette HE, Lave JR, Kearney DH, Clbrn DK, Kurs-Lasky M, Haralam MA, Byers CJ, Zffel LM, Fabian IA, Bernard BS, Kerr JD. Effectiveness f inactivated influenza vaccine in preventing acute titis media in yung children: a randmized cntrlled trial. JAMA. 2003;290(12): (PDF link) Jacksn LA, Gaglani MJ, Keyserling HL, Balser J, Buveret N, Fries L, Treanr JJ. Safety, efficacy, and immungenicity f an inactivated influenza vaccine in healthy adults: a randmized, placeb-cntrlled trial ver tw influenza seasns. BMC Infect Dis. 2010;10:71. (PDF link) Mnt AS, Hrnbuckle K, Ohmit SE. Influenza vaccine effectiveness amng elderly nursing hme residents: a chrt study. Am J Epidemil. 2001;154(2): (PDF link) Mnt AS, Ohmit SE, Petrie JG, Jhnsn E, Truscn R, Teich E, Rtthff J, Bultn M, Victr JC. Cmparative efficacy f inactivated and live attenuated influenza vaccines. N Engl J Med. 2009;361(13): (PDF link) Neuzil KM, Dupnt WD, Wright PF, Edwards KM. Efficacy f inactivated and cld-adapted vaccines against influenza A infectin, 1985 t 1990: the pediatric experience. Pediatr Infect Dis J. 2001;20(8): Prepared by Influenza Divisin Page 7 f 7