HAI and NAI as Correlates of Protection After Influenza Vaccination Arnold S. Monto Thomas Francis Jr. Professor University of Michigan School of Public Health Ann Arbor, Michigan
Having Correlates is Desirable Correlates are useful for early evaluation of new or modified vaccines. Conducting efficacy trials is challenging, because of the unpredictable nature of influenza. It is currently unethical to conduct placebo controlled trials in many population groups in much of the developed world, in particular in the US because of the universal recommendation. Observational studies especially in risk groups, are subject to different interpretations. Sera have not commonly been collected
Challenges to establishing correlates Different vaccines may have different correlates; this problem may increase as diversity of vaccines increases Antigenic drift may affect how well correlates predict differentially With effective vaccines, the number of failures will be small With HAI being such a strong predictor, other correlates, such as NAI, may be difficult to establish. Correlates may vary by age, requiring study in different age/risk groups. They may also vary by type (B rarely studied)
Study of Early Influenza Vaccine University of Michigan Military Service Unit, 1943 Inactivated influenza vaccine containing two type A strains (PR8 and Weiss) and B/Lee Placebo controlled design HAI antibody pre and 14 days post vaccination Outbreak early type A only. Combined endpoint some virus identification-some clinical
Distribution of men according to companies, places of residence and activities Company Strength Location of quarters Location of mess University studies A 239 Dormitory A Dorm. A Language B 34 30 33 C 112 44 45 40 Fraternity house 1 2 3 Dormitory B Fraternity 4 5 6 Union Union Engineering Language D 263 Dormitory A Dorm. A Language E 328 Dormitory A Dorm. A Engineering F 40 66 40 50 30 G 282 37 Fraternity house 7 8 9 10 11 Dormitory C Fraternity house 12 Union Dorm. C Dorm. C Language Medicine Dentistry Sta. Comp. 63 Private rooms and apartments Union or Dorm. A None Salk et al. Am J Hyg 1945;42:57-93.
Incidence of respiratory disease in the University of Michigan A.S.T.P. unit, 1943-1944 Controls Incidence - Percent 11 10 9 8 7 6 5 4 3 2 1 0 30 Oct. 6 Nov. 13 Nov. 20 Nov. 27 Nov. 4 Dec. 11 Dec. 18 Dec. 25 Dec. 1 Jan. Vaccinated Salk et al. Am. J. Hyg. 1945;42:57-93.
Percentage distribution of individuals, before and after the epidemic, in relation to zones of serum antibody concentration associated with different frequencies of illness Antibody zone (Weiss strain) Frequency of illness Control population Vaccinated population Cont. and vacc. combined Before After Before After Before After <32 to 64 128 to 1,024 2,048 or above 26.1 to 7.7 3.5 to 1.0 0 47.6 52.4 0 25.4 70.1 4.5 2.4 80.6 17.0 2.8 85.8 11.4 25.0 66.5 7.5 14.1 77.9 8.0 Salk et al. Am J Hyg 1945;42:57-93.
Protective Efficacy of Inactivated Influenza Vaccines 1943-1969 100 90 Percent Protection 80 70 60 50 40 30 20 10 0 A(H1N1) 1943 B 1945 A(H1N1) 1950 A(H1N1) 1951 A(H1N1) 1953 B 1955 A(H1N1) 1957 A(H2N2) 1957 A(H2N2) 1958 B 1958 A(H2N2) 1960 A(H3N2) 1968 A( H3N2) 1969 Year, Type of Virus
Significant Rise in Titer among those with PCR Positive H3N2 Influenza in the 2004-2005, 2005-2006 and 2007-2008 seasons Serologic Confirmation N (%) All Symptomatic Illnesses Positive by PCR Placebo (n=41) 37 (90) LAIV (n=77) 67 (87) TIV (n=39) 9 (23) Total (n=157) 113(72) Petrie et al. J. Infect Diseases 2011;203:1309-15
Correlation between incidence of influenza and acute-phase FM1 agglutination-inhibiting antibodies among 2,854 men who had not received influenza A or A-prime vaccine Titer Distribution of personnel by titers Percent of men Estimated number of men Cases of influenza Estimated number of cases Estimated incidence <8 11 313 58 18.3 8 25 711 54 7.6 16 42 1,199 18 1.5 32 18 502 8 1.6 64 3 86 0 0.0 128 or more 2 57 0 0.0 Meiklejohn et al. Am J Hyg 1952;55:12-21.
Infection rates of 462 volunteers challenged with B/Eng/13/65, in relation to their pre-challenge titers of serum HI antibody. Hobson et al. J Hyg (Lond) 1972; 70:767-777.
Study Objectives: FLUVACS (Michigan) To evaluate the absolute and relative efficacies of TIV and LAIV in preventing laboratory confirmed symptomatic influenza caused by circulating strains (whether antigenically similar or dissimilar to strains included in the vaccines).
Design: Randomized, double blind, placebocontrolled, community-based trial Healthy adults, 18 to 49 years Interventions: licensed TIV [Fluzone, injection] or LAIV [Flumist, nasal spray], injection or nasal spray placebo, vaccine to placebo ratio 5:1 Blood specimens: collected pre-intervention, one month post-intervention and postinfluenza season Surveillance (November April): specimens collected from participants with influenzalike illness
Results year 4 (2007-2008): Participant population: 1,952 enrolled subjects were randomly assigned and received a vaccine or placebo. Mean age 23 years (range 18-48) 62% were women 814 received TIV; 813 received LAIV; 325 received placebo Previous subjects could participate but were re-randomized
Results 2007-2008: 119 (6.1%) participants had culture or PCR confirmed symptomatic influenza All 107 type A (H3N2) viruses were genotypically A/Brisbane/10/2007 By HAI, some were high reactors to vaccine strain A/Wisconsin/67/2005, some low reactors Only 1 type A (H1N1) virus identified, antigenically related to the vaccine virus, A/Brisbane/59/2007 All 11 type B viruses were from the B/Yamagata lineage while the vaccine virus was B/Victoria-like Monto et al. NEJM. 2009; 361:1260
Efficacies of TIV and LAIV against type A and B influenza, Michigan, 2007-2008 Endpoint Incidence of Influenza Vaccine efficacy (95% CI) TIV N=813 LAIV N=814 Placebo N=325 TIV vs. Placebo LAIV vs. Placebo TIV vs. LAIV Culture positive 21 (2.6) 38 (4.7) 31 (9.5) 73 (51-85) 51 (19-70) 45 (3-69) PCR positive 28 (3.4) 56 (6.9) 35 (10.8) 68 (46-81) 36 (0-59) 50 (20-69) Positive culture or PCR 28 (3.4) 56 (6.9) 35 (10.8) 68 (46-81) 36 (0-59) 50 (20-69) Monto et al. NEJM. 2009; 361:1260
Efficacy of TIV and LAIV against type A and type B influenza viruses, Michigan, 2007-2008 Endpoint Influenza A Culture and/or PCR positive Influenza B Cumulative Incidence of Influenza TIV N=813 22 (2.7) LAIV N=814 55 (6.8) Placeb o N=325 31 (9.5) Vaccine efficacy (95% CI) TIV vs. Placebo 72 (49 to 84) LAIV vs. Placebo 29 (-14 to 55) TIV vs. LAIV 60 (33 to 77) Culture and/or PCR positive 6 (0.7) 1 (0.1) 4 (1.2) 40 (-189 to 86) 90 (-1 to 100) -501 (-27530 to 27) Monto et al. NEJM. 2009; 361:1260
Relation of pre-outbreak antineuraminidase (A.N.) antibody to infections during 1968-69 Hong Kong influenza outbreak A.N. titer pre-outbreak (reciprocal) No. with titer Total infected No. % < 8 159 62 39.0 8 (trace) 56 16 28.6 8 35 9 25.7 16 24 5 20.8 Total 274 92 33.6 Monto et al. Lancet 1973; 1:623-625
Vaccine and infection immune responses measured by hemagglutination inhibition (HAI), microneutralization (MN), and neuraminidase inhibition (NAI) assays by intervention. Placebo N (%) IIV N (%) LAIV N (%) Vaccine Immune Response a HAI Assay (N=497) 2 (2.2) 137 (77.0) 48 (21.2) MN Assay (N=171) 2 (3.4) 35 (67.3) 10 (16.7) NAI Assay (N=497) 5 (5.4) 65 (36.5) 14 (6.2) Infection Immune Response b among Cases c,d HAI Assay (N=103) 28 (96.5) 4 (18.2) 40 (76.9) MN Assay (N=81) 26 (89.7) 6 (27.3) 20 (66.7) NAI Assay (N=103) 22 (75.9) 9 (40.9) 33 (63.5) a 4-fold rise in HAI, MN, or NAI titer as measured from Pre-vaccination to Post-vaccination serum b 4-fold rise in HAI, MN, or NAI titer as measured from Post-vaccination to Post-season serum c Influenza A (H3N2) infection confirmed by RT-PCR or isolation in cell culture. d Influenza A (H3N2) infections were identified in 29 of 92 placebo, 22 of 178 IIV, and 52 of 227 LAIV recipients.
Post-vaccination hemagglutination inhibition (HAI) and neuraminidase inhibition (NAI) titers and percent influenza A (H3N2) positive by titer among placebo recipients.
Post-vaccination hemagglutination inhibition (HAI) and neuraminidase inhibition (NAI) titers and percent influenza A (H3N2) positive by titer among inactivated influenza vaccine (IIV) recipients.
Post-vaccination hemagglutination inhibition (HAI) and neuraminidase inhibition (NAI) titers and percent influenza A (H3N2) positive by titer among live-attenuated influenza vaccine (LAIV) recipients.
Post-vaccination microneutralization (MN) titers and percent influenza A (H3N2) positive by titer among placebo recipients.
Post-vaccination microneutralization (MN) titers and percent influenza A (H3N2) positive by titer among inactivated influenza vaccine (IIV) recipients.
Post-vaccination microneutralization (MN) titers and percent influenza A (H3N2) positive by titer among live-attenuated influenza vaccine (LAIV) recipients.
Correlation of log 2 hemagglutination inhibition (HAI), microneutralization (MN), and neuraminidase inhibition (NAI) titers at pre-vaccination, post-vaccination, and postseason time points by intervention group. Pre-Vaccination Post-Vaccination Post-Season Placebo HAI MN NAI HAI MN NAI HAI MN NAI Correlation HAI 1.00 0.87 0.47 HAI 1.00 0.87 0.55 HAI 1.00 0.84 0.53 >0.75 MN 1.00 0.41 MN 1.00 0.51 MN 1.00 0.56 0.50-0.75 NAI 1.00 NAI 1.00 NAI 1.00 <0.50 Inactivated Influenza Vaccine HAI MN NAI HAI MN NAI HAI MN NAI HAI 1.00 0.87 0.40 HAI 1.00 0.78 0.37 HAI 1.00 0.78 0.31 MN 1.00 0.46 MN 1.00 0.38 MN 1.00 0.40 NAI 1.00 NAI 1.00 NAI 1.00 Live-Attenuated Influenza Vaccine HAI MN NAI HAI MN NAI HAI MN NAI HAI 1.00 0.81 0.42 HAI 1.00 0.88 0.37 HAI 1.00 0.87 0.45 MN 1.00 0.61 MN 1.00 0.52 MN 1.00 0.41 NAI 1.00 NAI 1.00 NAI 1.00
Seroconversion After Seasonal LAIV Does Not Correlate Well with Efficacy Study A (H1N1) responses A (H3N2) responses B responses AV006 Yr 1 48 Did not circulate 53 96 68 91 AV006 Yr 2 41 Did not circulate 5 100 30 Did not circulate D153-P501 Yr 1 60 81 61 90 59 44 D153-P501 Yr 2 28 100 32 86 26 62 D153-P502 Yr 1 47 92 60 100 79 73 D153-P502 Yr 2 50 90 25 90 38 82 D153-P504 Yr 1 56 Did not circulate 80 73 69 81 D153-P504 Yr 2 28 94 14 49-102 10 Subjects seroresponding (%) Absolute efficacy against matched strains (%) 04/14/2008 6:00pm eslide - P4815 - MedImmune Template
Moving forward Revisit the precise role of HAI antibody in protection using contemporary endpoints; add NAI to these evaluations. Understand better the role of antigenic drift, and the role of protection afforded by anti-neuraminidase antibody in that situation Identify whether correlates are different with different vaccine formulations and vaccine match; further work necessary for LAIV Use efficacy trials to provide updated data on protection with sharing of material. What should the role be of observational studies with infection confirmed?