High-Dose Flu Vaccine has Increased Immunogenicity in HIV Patients

By Richard R. Watkins, MD, MS, FACP, Division of Infectious Diseases, Akron General Medical Center, Akron, OH; Associate Professor of Internal Medicine, Northeast Ohio Medical University, Rootstown, OH.

Dr. Watkins reports no financial relationships in this field of study.

Synopsis: A single-center, parallel, double-blind, randomized trial that included HIV patients 18 years and older compared the rate of seroprotection between standard dose and high dose influenza trivalent vaccine. The seroprotection rate was greater in the high-dose group for H1N1 (96% vs. 87%), H3N2 (96% vs. 92%), and influenza B (91% vs. 80%). It is unclear whether these findings correlate with preventing clinical influenza.

Source: McKittrick N, et al. Improved immunogenicity with high-dose seasonal influenza vaccine in HIV-infected persons. Annals Intern Med 2013;158:19-26.

Seasonal influenza is a major worldwide threat to human health. Vaccination against influenza is an important intervention to prevent disease especially in vulnerable populations, such as the elderly and immunocompromised individuals. In particular, HIV-infected patients are at increased risk for complications from influenza including hospitalization, prolonged illness, and death. Unfortunately, antibody responses after influenza immunization are lower in HIV-infected patients than in the general population. It is believed that lower CD4 counts and the presence of HIV viremia contribute to lower immunogenicity in this group. Elderly patients have similarly reduced immune responses to influenza vaccination and increased doses of antigen can lead to higher antibody titers. A previous study that used two double doses (30 mcg/strain) of influenza vaccine in HIV-infected patients found no improvement in immunogenicity.1

McKittrick and colleagues sought to determine if high dose (HD) trivalent vaccine (60 mcg/strain, four times the standard dose of 15 mcg) would result in improved immunogenicity in their HIV-infected patients compared to the standard dose (SD) trivalent vaccine. The primary outcome of the study was the proportion of patients with seroprotective antibody levels at 21 to 28 days after vaccination. The primary safety endpoint was the frequency and intensity of adverse events up to 28 days post-vaccination. Secondary endpoints included the seroconversion rate and the geometric mean titers before and after receiving the vaccine. Of 195 participants enrolled, 192 completed the second visit. Ninety-seven received the HD vaccine and 93 the standard dose. Participants were mostly men, African-American, receiving HAART, and had undetectable HIV RNA viral loads. Approximately 10% had current CD4 counts less than 0.200 X 109 cells/L. For study purposes the authors defined seroconversion as a 4-fold increase in antibody titer from baseline or an increase in titer from ≤ 1:10 to 1:40 and seroprotection as an antibody titer ≥ 1:40.

The percentage of patients that achieved seroprotective antibody titers was greater for those who received the HD vaccine, with significant (P < 0.05) increases for the H1N1 and influenza B strains. For the H1N1 strain, 96% of the HD group vs 87% of the SD group developed protective antibodies (P = 0.029); for H3N2, 96% of the HD group vs the 92% of the SD group developed protective antibodies (P = 0.32); and for influenza B, 91% of the HD group vs 80% of the SD group developed protective antibodies (P = 0.03).

Furthermore, seroconversion rates were greater in the HD group than in the SD group for H1N1 (75% vs. 59%), H3N2 (78% vs. 74%), and influenza B (56% vs. 34%) strains. Participants with CD4 counts less than 0.200 X 109 cells/L were less responsive to both the HD and SD vaccines, with fewer achieving seroprotective levels compared to participants with higher counts. Logistic regression models revealed that baseline antibody titer for the corresponding strain and randomization to the HD group always resulted in seroconversion. Both vaccines were well-tolerated with no significant differences in local or systemic reactions and no serious adverse events occurred with either one.


This study suggests it is possible to increase protective antibody titers for influenza in HIV-infected patients through the use of high dose seasonal influenza trivalent vaccine. If further randomized trials confirm these data, it will be an important advancement for preventing the sequelae of influenza in HIV-infected patients. One limitation of the study was the finding that half of the patients had evidence of protective titers at baseline. This likely resulted in a higher seroprotection rate at the end of the study than would have been normally expected. Another limitation was that the authors did not measure the incidence of clinical influenza. While it seems logical that higher seroconversion and seroprotection would result in lower risk for clinical disease, this assumption is speculative and unproven based on the study.

The overall clinical effectiveness of the HD vaccine remains uncertain. While investigators demonstrated improved immune response in elderly patients,2 outcome data showing significantly improved protection against influenza is not yet available. Results from clinical trials on vaccine efficacy are not expected for another 2 to 3 years. Indeed, neither the CDC nor the ACIP have recommended one influenza dose over the other. The HD vaccine costs approximately double the SD vaccine, although Medicare will pay for either one. Another potential drawback for the HD vaccine seems to be more side effects, such as myalgias, headaches and pain at the injection site although there was no difference between the HD and SD doses in the present study. The theoretical benefits of the HD vaccine in HIV-infected individuals seem to justify its use with little downside, although it is certainly reasonable for clinicians to wait until results of further clinical trials are known.


  1. Cooper C, et al. Immunogenicity is not improved by increased antigen dose or booster dosing of seasonal influenza vaccine in a randomized trial of HIV infected adults. PloS One 2011;6:e17758.
  2. Diazgranados CA, et al. High-dose trivalent influenza vaccine compared to standard dose vaccine in elderly adults: safety, immunogenicity and relative efficacy during the 2009-2010 season. Vaccine 2013; 31:861-866.