Noah McKittrick, MD; Ian Frank, MD; Jeffrey M. Jacobson, MD; C. Jo White, MD; Deborah Kim, RPh; Rosemarie Kappes, RN, MPH; Carol DiGiorgio, RN; Thomas Kenney, BS; Jean Boyer, PhD; Pablo Tebas, MD; for the Center for AIDS Research
Disclaimer: Sanofi Pasteur was not involved in the study design or the analysis.
Grant Support: In part by grant U01-AI069467 from the National Institute of Allergy and Infectious Diseases and grant P30-AI045008 from the Center for AIDS Research to the University of Pennsylvania.
Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-1043.
Reproducible Research Statement: Study protocol, statistical code, and data set: Available from Dr. Tebas (e-mail, email@example.com).
Requests for Single Reprints: Pablo Tebas, MD, University of Pennsylvania, AIDS Clinical Research Unit, 502 Johnson Pavillion, 3610 Hamilton Walk, Philadelphia, PA 19104.
Current Author Addresses: Dr. McKittrick: Jefferson Hospital Ambulatory Practice, 833 Chestnut Street, Suite 220, Philadelphia, PA 19107.
Drs. Frank, White, Boyer, and Tebas; Ms. Kim, Ms. Kappes, Ms. DiGiorgio, and Mr. Kenney: University of Pennsylvania, AIDS Clinical Research Unit, 502 Johnson Pavillion, 3610 Hamilton Walk, Philadelphia, PA 19104.
Dr. Jacobson: Partnership Comprehensive Care Practice, 1427 Vine Street, 3rd Floor, Philadelphia, PA 19102.
Author Contributions: Conception and design: J.M. Jacobson, C.J. White, P. Tebas.
Analysis and interpretation of the data: N. McKittrick, I. Frank, J.M. Jacobson, C.J. White, P. Tebas.
Drafting of the article: N. McKittrick, J. Boyer, P. Tebas.
Critical revision of the article for important intellectual content: N. McKittrick, I. Frank, J.M. Jacobson, C.J. White, P. Tebas.
Final approval of the article: N. McKittrick, I. Frank, J.M. Jacobson, C.J. White, P. Tebas.
Provision of study materials or patients: N. McKittrick, I. Frank, J.M. Jacobson, D. Kim, R. Kappes, C. DiGiorgio, T. Kenney, P. Tebas.
Statistical expertise: P. Tebas.
Obtaining of funding: P. Tebas.
Administrative, technical, or logistic support: N. McKittrick, I. Frank, J.M. Jacobson, C.J. White, D. Kim, R. Kappes, C. DiGiorgio, T. Kenney, P. Tebas.
Collection and assembly of data: N. McKittrick, J.M. Jacobson, C. DiGiorgio, T. Kenney, J. Boyer, P. Tebas.
HIV-infected persons have less robust antibody responses to influenza vaccines.
To compare the immunogenicity of high-dose influenza vaccine with that of standard dosing in HIV-positive participants.
Randomized, double-blind, controlled trial. (ClinicalTrials.gov: NCT01262846)
The MacGregor Clinic of the Hospital of the University of Pennsylvania, Philadelphia, from 27 October 2010 to 27 March 2011.
HIV-infected persons older than 18 years.
Participants were randomly assigned to receive either a standard dose (15 mcg of antigen per strain) or a high dose (60 mcg/strain) of the influenza trivalent vaccine.
The primary end point was the rate of seroprotection, defined as antibody titers of 1:40 or greater on the hemagglutination inhibition assay 21 to 28 days after vaccination. The primary safety end point was frequency and intensity of adverse events. Secondary end points were seroconversion rate (defined as a greater than 4-fold increase in antibody titers) and the geometric mean antibody titer.
195 participants enrolled, and 190 completed the study (93 in the standard-dose group and 97 in the high-dose group). The seroprotection rates after vaccination were higher in the high-dose group for the H1N1 (96% vs. 87%; treatment difference, 9 percentage points [95% CI, 1 to 17 percentage points]; P = 0.029), H3N2 (96% vs. 92%; treatment difference, 3 percentage points [CI, −3 to 10 percentage points]; P = 0.32), and influenza B (91% vs. 80%; treatment difference, 11 percentage points [CI, 1 to 21 percentage points]; P = 0.030) strains. Both vaccines were well-tolerated, with myalgia (19%), malaise (14%), and local pain (10%) the most frequent adverse events.
The effectiveness of the vaccine in preventing clinical influenza was not evaluated. The number of participants with CD4 counts less than 0.200 × 109 cells/L was limited.
HIV-infected persons reach higher levels of influenza seroprotection if vaccinated with the high-dose trivalent vaccine than with the standard-dose.
National Institute of Allergy and Infectious Diseases and Center for AIDS Research of the University of Pennsylvania.
Compared with the general population, HIV-infected patients may have greater morbidity and mortality from influenza and a decreased response to seasonal influenza vaccine.
In a randomized, controlled trial, HIV-infected patients who received a quadruple dose of seasonal influenza vaccine had a higher antibody response and greater seroconversion rate than did those who received a standard dose. Adverse event rates were similar in the 2 intervention groups.
The trial was not powered to determine clinical efficacy or to detect differences in the occurrence of less common adverse events.
Administering a quadruple dose of seasonal influenza is a possible approach to seasonal influenza vaccination of HIV-infected patients.
Study flow diagram.
HD = high dose; SD = standard dose.
* Fluzone is manufactured by Sanofi Pasteur (Bridgewater, New Jersey).
Prevaccination and Postvaccination GMTs
Seroconversion and Seroprotection Rates After Vaccination
Appendix Table 1.
Seroconversion and Seroprotection Rates in Participants With CD4 Counts Less Than 0.200 × 109 cells/L
Appendix Table 2.
Logistic Regression Model Data
Adverse Events During the Trial
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Yehuda Z. Cohen
Beth Israel Deaconess Medical Center
January 16, 2013
Antibody response does not predict efficacy in HIV-infected persons
While the study by McKittrick and colleagues (1) demonstrated a superior antibody response to a high-dose inactivated influenza vaccine in HIV-infected persons, this finding is unlikely to have significant clinical implications. The Fluzone High-Dose vaccine used in the study received accelerated approval by the FDA for adults greater than 65 years of age in December 2009 without prior efficacy trials, and superior efficacy compared to the standard dose vaccine has yet to be established (2).
It remains unclear whether the improved antibody response elicited by the vaccine will result in increased protection in older adults, as cellular immunity has been found to be a better correlate of protection in this population (3).
Similarly, the antibody response to the influenza vaccine in HIV-infected individuals does not correlate well with vaccine efficacy. While HIV-infected individuals have consistently been found to have a poor antibody response to the standard dose vaccine, vaccine efficacy in this population appears to be quite good, as demonstrated by two randomized, double blind, controlled trials.
The first trial, based in the United States, found 100% vaccine efficacy in HIV-infected individuals (4), and the second trial, based in South Africa, found 75.5% vaccine efficacy (5). Of note, in the South African trial, seroconversion rates were only in the 50-60% range, reinforcing the notion that antibody response does not reliably predict vaccine efficacy in HIV-infected persons.
1. McKittrick N, Frank I, Jacobson JM, White J, Kim D, Kappes R, DiGiorgio C, Kenney T, Boyer J, Tebas P. Improved Immunogenicity With High-Dose Seasonal Influenza Vaccine in HIV-Infected Persons: A Single-Center, Parallel, Randomized Trial. Ann Intern Med. 2013;158(1):19-26.
2. DiazGranados CA, Dunning AJ, Jordanov E, Landolfi V, Denis M, Talbot HK. High-dose trivalent influenza vaccine compared to standard dose vaccine in elderly adults: Safety, immunogenicity and relative efficacy during the 2009–2010 season. Vaccine. 2012; http://dx.doi.org/10.1016/j.vaccine.2012.12.013
3. McElhaney JE, Xie D, Hager WD, Barry MB, Wang Y, Kleppinger A, Ewen C, Kane KP, Bleackley RC. T cell responses are better correlates of vaccine protection in the elderly. J Immunol. 2006;176(10):6333-9.
4. Tasker SA, Treanor JJ, Paxton WB, Wallace MR. Efficacy of influenza vaccination in HIV-infected persons. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1999;131(6):430-3.
5. Madhi SA, Maskew M, Koen A, Kuwanda L, Besselaar TG, Naidoo D, Cohen C, Valette M, Cutland CL, Sanne I. Trivalent inactivated influenza vaccine in African adults infected with human immunodeficient virus: double blind, randomized clinical trial of efficacy, immunogenicity, and safety. Clin Infect Dis. 2011;52(1):128-37.
Marta C Nunes, Shabir A Madhi
Department of Science and Technology, Vaccine Preventable Diseases Unit: University of the Witwatersrand, Johannesburg, South Africa; Medical Research Council Respiratory and Meningeal Pathogens Resea
January 30, 2013
Is high-dose seasonal trivalent inactivated influenza vaccine required in HIV-infected adults?
The article by McKittrick et al. reported heightened humoral immune responses, measured by hemagglutinin inhibition (HI) assays, to two influenza-strains among HIV-infected adults randomized to high-dose (60mcg per antigen) compared to standard-dose (15mcg per antigen) trivalent influenza vaccine (TIV) . Whilst appreciating the need to develop improved influenza-vaccine formulations generally, it remains debatable whether the enhanced humoral immunogenicity in their study can be extrapolated to higher efficacy in HIV-infected adults. This is particularly pertinent in the absence of corroborating data of high-dose-TIV being more efficacious against influenza confirmed-illness in immuncompromized individuals. Also, evaluation of HI responses alone is only modestly predictive of protection against influenza-illness . As noted, the effect of vaccination on cell-mediated immune response, would have been useful to corroborate the clinical applicability of their findings.
While the authors are correct that most clinical-studies on influenza-vaccine in immunocompromized individual have not evaluated efficacy, we draw their attention to a study which was powered to evaluate clinical-efficacy and immunogenicity among South African HIV-infected adults . The South African cohort was comparable to the McKittrick et al. study in relation to proportion on ART, supressed HIV viral-load and CD4 immunological-status at vaccination. Although the South African study evaluated TIV involving different vaccine-strains, seroconversion rates one-month post-vaccination in the high-dose-arm were similar to that among South Africans on stable-ART (i.e. H1N1 75% vs. 71%, H3N2 78% vs. 71%, influenza B 56% vs. 63%). Also, despite the proportion of South Africans with sero-protective titers post-vaccination being modest (H1N1 57%, H3N2 63% and influenza-B 68%; Madhi at al., unpublished data), the efficacy against influenza confirmed-illness was 75% (95%CI: 14-93) .This study, hence, demonstrated efficacy of standard-dose in HIV-infected adults of a magnitude similar to healthy-adults (70-90%) .
Furthermore, the vaccine-efficacy estimate in South Africa was similar to results of a meta-analysis on TIV-efficacy in HIV-infected adults, which was however limited by small sample-sizes and varying endpoints . The point-estimate of individuals with H1N1 sero-protective titers post-vaccination in South Africa (57%) was lower than the vaccine-efficacy against confirmed-H1N1 illness (73%). This, we believe, underscores the need to also measure cell-mediated immune responses, when evaluating the immunogenicity of different vaccine-formulations in the absence of robust clinical-efficacy endpoints.
Although McKittrick et al. are correct that there is no biological-reason for standard-dose to be more efficacious that high-dose TIV, the relative value of high-dose TIV should be corroborated by other immunogenicity and or efficacy measures to warrant advocating high-dose TIV for HIV-infected adults.
1. McKittrick, N., et al., Improved Immunogenicity With High-Dose Seasonal Influenza Vaccine in HIV-Infected Persons: A Single-Center, Parallel, Randomized Trial. Ann Intern Med, 2013. 158(1): p. 19-26
2. Hobson, D., et al., The role of serum haemagglutination-inhibiting antibody in protection against challenge infection with influenza A2 and B viruses. J Hyg (Lond), 1972. 70(4): p. 767-77
3. Madhi, S.A., et al., Trivalent inactivated influenza vaccine in African adults infected with human immunodeficient virus: double blind, randomized clinical trial of efficacy, immunogenicity, and safety. Clin Infect Dis, 2011. 52(1): p. 128-37
4. Jefferson, T., et al., Vaccines for preventing influenza in healthy adults. Cochrane Database Syst Rev, 2010(7): p. CD0012695. Atashili, J., L. Kalilani, and A.A. Adimora, Efficacy and clinical effectiveness of influenza vaccines in HIV-infected individuals: a meta-analysis. BMC Infect Dis, 2006. 6: p. 138
McKittrick N, Frank I, Jacobson JM, White CJ, Kim D, Kappes R, et al. Improved Immunogenicity With High-Dose Seasonal Influenza Vaccine in HIV-Infected Persons: A Single-Center, Parallel, Randomized Trial. Ann Intern Med. 2013;158:19–26. doi: 10.7326/0003-4819-158-1-201301010-00005
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Published: Ann Intern Med. 2013;158(1):19-26.
HIV, Infectious Disease, Influenza, Prevention/Screening, Vaccines/Immunization.
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