Lancet: DNA priming and influenza vaccine immunogenicity: two phase 1 open label randomized clinical trials

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The Lancet Infectious Diseases, Early Online Publication, 4 October 2011
doi:10.1016/S1473-3099(11)70240-7Cite or Link Using DOI
DNA priming and influenza vaccine immunogenicity: two phase 1 open label randomised clinical trials
Julie E Ledgerwood DO ?a Corresponding AuthorEmail Address, Chih-Jen Wei PhD ?a, Zonghui Hu PhD b, Ingelise J Gordon RN a, Mary E Enama PA-C a, Cynthia S Hendel CRNP a, Patrick M McTamney PhD a, Melissa B Pearce PhD c, Hadi M Yassine PhD a, Jeffrey C Boyington PhD a, Robert Bailer PhD a, Terrence M Tumpey PhD c, Richard A Koup MD a, John R Mascola MD a, Gary J Nabel MD a, Barney S Graham MD a, the VRC 306 Study Team
Summary
Background
Because the general population is largely naive to H5N1 influenza, antibodies generated to H5 allow analysis of novel influenza vaccines independent of background immunity from previous infection. We assessed the safety and immunogenicity of DNA encoding H5 as a priming vaccine to improve antibody responses to inactivated influenza vaccination.
Methods
In VRC 306 and VRC 310, two sequentially enrolled phase 1, open-label, randomised clinical trials, healthy adults (age 18?60 years) were randomly assigned to receive intramuscular H5 DNA (4 mg) at day 0 or twice, at day 0 and week 4, followed by H5N1 monovalent inactivated vaccine (MIV; 90 μg) at 4 or 24 weeks, and compared with a two-dose regimen of H5N1 MIV with either a 4 or 24 week interval. Antibody responses were assessed by haemagglutination inhibition (HAI), ELISA, neutralisation (ID80), and immunoassays for stem-directed antibodies. T cell responses were assessed by intracellular cytokine staining. After enrolment, investigators and individuals were not masked to group assignment. VRC 306 and VRC 310 are registered with ClinicalTrials.gov, numbers NCT00776711 and NCT01086657, respectively.
Findings
In VRC 306, 60 individuals were randomly assigned to the four groups (15 in each) and 59 received the vaccinations. In VRC 310, of the 21 individuals enrolled, 20 received the vaccinations (nine received a two-dose regimen of H5N1 MIV and 11 received H5 DNA at day 0 followed by H5N1 MIV at week 24). H5 DNA priming was safe and enhanced H5-specific antibody titres following an H5N1 MIV boost, especially when the interval between DNA prime and MIV boost was extended to 24 weeks. In the two studies, DNA priming with a 24-week MIV boost interval induced protective HAI titres in 21 (81%) of 26 of individuals, with an increase in geometric mean titre (GMT) of more than four times that of individuals given the MIV-MIV regimen at 4 or 24 weeks (GMT 103?206 vs GMT 27?33). Additionally, neutralising antibodies directed to the conserved stem region of H5 were induced by this prime-boost regimen in several individuals. No vaccine-related serious adverse events were recorded.
Interpretation
DNA priming 24 weeks in advance of influenza vaccine boosting increased the magnitude of protective antibody responses (HAI) and in some cases induced haemagglutinin-stem-specific neutralising antibodies. A DNA-MIV vaccine regimen could enhance the efficacy of H5 or other influenza vaccines and shows that anti-stem antibodies can be elicited by vaccination in man.
Funding
National Institutes of Health.

http://www.lancet.com/journals/laninf/article/PIIS1473-3099(11)70240-7/fulltext

 

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Re: Lancet: DNA priming and influenza vaccine immunogenicity: two phase 1 open label randomized clinical trials

Priming with DNA vaccine makes avian flu vaccine work better

NIH study also provides proof of concept for universal influenza vaccine

The immune response to an H5N1 avian influenza vaccine was greatly enhanced in healthy adults if they were first primed with a DNA vaccine expressing a gene for a key H5N1 protein, researchers say. Their report describes results from two clinical studies conducted by researchers from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

A majority of study volunteers who received the DNA vaccine 24 weeks before receiving a booster vaccine made from whole, inactivated H5N1 virus produced high levels of antibodies thought to be protective against the globular head region of a protein called hemagglutinin (HA). Traditional seasonal influenza vaccines are designed to elicit antibodies to the head region of HA, but it changes each year and so vaccines must be repeated annually to maintain immunity. In some volunteers, the prime-boost vaccine regimen also spurred production of broadly neutralizing antibodies aimed at the HA stem, a region that is relatively constant across many strains of influenza viruses.

"The results of these studies demonstrate an important proof of concept, in that it is possible to elicit broadly neutralizing influenza antibodies in humans through vaccination," said NIAID Director Anthony S. Fauci, M.D. "These findings mark an early but significant milestone on the pathway to a universal influenza vaccine that provides protection against multiple virus strains."

The findings from the Phase I clinical trials appear in an article online Oct. 4 in The Lancet Infectious Diseases. Gary J. Nabel, M.D., Ph.D., director of the NIAID Vaccine Research Center (VRC), and his colleagues developed the H5N1 influenza DNA vaccine. The other vaccine used in the study was made by Sanofi Pasteur, located in Swiftwater, Pa.

In 2010, VRC studies in mice, ferrets and monkeys showed that a DNA prime-boost influenza vaccine regimen can elicit broadly neutralizing antibodies directed against the HA stem. "Now we see that it is possible to elicit HA stem-directed antibodies in people as well," said Dr. Nabel. The VRC researchers are hoping to apply this approach to research on vaccines against other seasonal and pandemic influenza strains too.

Since 2003, there have been 564 confirmed cases of human H5N1 influenza infection and 330 associated deaths worldwide, according to the most recent figures from the World Health Organization. Developing an effective vaccine against H5N1 influenza has proved difficult, because vaccines containing the whole, inactivated virus often fail to generate high levels of protective antibodies in people. The VRC studies confirm that volunteers who received only two doses of an inactivated H5N1 virus vaccine spaced 24 weeks apart produced only modest levels of H5N1-directed antibodies.

"Our study was designed to test whether a gene-based DNA vaccine could prime the immune system and lead to a better antibody response following boosting with an inactivated H5N1 vaccine," said, Julie Ledgerwood, D.O., co-lead author of the new report and the study's principal investigator, of the VRC Clinical Trials Core. "We found that the DNA primer vaccine improved the response to the inactivated H5N1 vaccine, but only when the boost interval was increased to 24 weeks."

Of the 26 volunteers who received the vaccines 24 weeks apart, 21 produced antibodies at levels predicted to protect them from H5N1 influenza. The antibody levels in that group were more than four times higher than those seen in volunteers who received two doses of inactivated H5N1 virus vaccine. Among volunteers who received their booster vaccine just four weeks after the DNA prime, only 4 out of 15 produced protective levels of antibodies.

In both clinical studies, the H5N1 DNA priming vaccine was found to be safe. That finding is consistent with data from previous clinical trials in which VRC DNA vaccines for HIV, Ebola, Marburg, West Nile virus, SARS and seasonal influenza have been tested and found to be safe in a total of 2,100 volunteers.

Next, the team will try to improve its DNA and other gene-based vaccines to more readily elicit antibodies directed at the stem region of the HA protein. The VRC group also is planning a larger trial of a prime-boost vaccine for seasonal influenza.

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Other VRC scientists who contributed to this study included Chih-Jen Wei, Ph.D., co-lead author of the paper, and Barney Graham, M.D., Ph.D., chief, VRC Clinical Trials Core and senior author of the paper. The publication reflects a collaboration between the NIAID (VRC) and the Centers for Disease Control and Prevention's Influenza Division.

For additional information about NIAID research on influenza, see the Influenza Web portal http://www.niaid.nih.gov/topics/flu/Pages/default.aspx. Also visit http://www.flu.gov/ for more information about seasonal and pandemic flu.

Further information about trial NCT00776711 (http://www.clinicaltrials.gov/ct2/show/NCT00776711?term=NCT00776711&rank=1) and trial NCT01086657 (http://www.clinicaltrials.gov/ct2/results?term=NCT01086657) is available at www.clinicaltrials.gov.

NIAID conducts and supports research?at NIH, throughout the United States, and worldwide?to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

References: JE Ledgerwood et al. DNA priming and influenza vaccine immunogenicity: two phase 1 open label randomized clinical trials. The Lancet Infectious Diseases DOI: 10.1016/S1473-3099(11)70240-7 (2011).

C-J Wei et al. Induction of broadly neutralizing H1N1 influenza antibodies by vaccination. Science DOI: 10.1126/science.1192517 (2010).

http://www.eurekalert.org/pub_releases/2011-10/nioa-pwd100311.php