Tweet
http://content.nejm.org/cgi/content/full/358/24/2573
A Clinical Trial of a Whole-Virus H5N1 Vaccine Derived from Cell Culture
<!-- AUTHOR_DISPLAY --> <center> Hartmut J. Ehrlich, M.D., Markus Müller, M.D., Helen M.L. Oh, M.D., Paul A. Tambyah, M.B., B.S., Christian Joukhadar, M.D., Emanuele Montomoli, Ph.D., Dale Fisher, F.R.A.C.P., Greg Berezuk, M.S., Sandor Fritsch, Ph.D., Alexandra Löw-Baselli, Ph.D., Nina Vartian, Ph.D., Roman Bobrovsky, Ph.D., Borislava G. Pavlova, Ph.D., Eva Maria Pöllabauer, M.D., Otfried Kistner, Ph.D., P. Noel Barrett, Ph.D., for the Baxter H5N1 Pandemic Influenza Vaccine Clinical Study Team </center> <!-- AUTHOR_DISPLAY --> A Clinical Trial of a Whole-Virus H5N1 Vaccine Derived from Cell Culture
<table align="right" border="0" cellpadding="0" cellspacing="0" width="200"> <tbody><tr> <td width="20"> </td> <td bgcolor="#336699"> <table style="width: 288px; height: 585px;" border="0" cellpadding="0" cellspacing="1"> <tbody><tr valign="top"> <td align="center" bgcolor="#e8e8d1" width="200">
</td> </tr><tr> <td> <table bgcolor="#ffffff" border="0" cellpadding="2" cellspacing="0" width="100%"> <tbody><tr valign="top"><td colspan="2">
</td></tr> <tr valign="top"><td align="center" valign="top" width="15">
</td><td valign="middle">Abstract</td></tr> <tr valign="top"><td align="center" valign="top" width="15"></td><td valign="middle"> PDF</td></tr> <tr valign="top"><td align="center" valign="top" width="15"></td><td valign="middle">PDA Full Text</td></tr> <tr valign="top"><td align="center" valign="top" width="15"></td><td valign="middle">PowerPoint Slide Set</td></tr> <tr valign="top"><td align="center" valign="top" width="15"></td><td valign="middle">Supplementary Material</td></tr> <tr valign="top"><td colspan="2"></td></tr> </tbody></table> </td> </tr> <tr> <td align="center" bgcolor="#e8e8d1" width="200">
</td> </tr> <tr> <td> <table bgcolor="#ffffff" border="0" cellpadding="2" cellspacing="0" width="100%"> <tbody><tr valign="top"><td colspan="2"></td></tr> <tr valign="top"><td align="center" valign="top" width="15"></td><td valign="middle">Perspective</td></tr><tr valign="top"><td align="center" valign="top" width="15">
</td><td valign="middle"><table border="0" cellpadding="0" cellspacing="0"><tbody><tr><td></td><td valign="middle">by Wright, P. F.</td></tr></tbody></table></td></tr> <tr valign="top"><td colspan="2"></td></tr> </tbody></table> </td> </tr> <tr> <td align="center" bgcolor="#e8e8d1" width="200">
</td> </tr> <tr> <td> <table bgcolor="#ffffff" border="0" cellpadding="2" cellspacing="0" width="100%"> <tbody><tr valign="top"><td colspan="2"></td></tr> <tr valign="top"><td align="center" valign="top" width="15"></td><td valign="middle">Add to Personal Archive</td></tr> <tr valign="top"><td align="center" valign="top" width="15"></td><td valign="middle">Add to Citation Manager</td></tr> <tr valign="top"><td align="center" valign="top" width="15"></td><td valign="middle">Notify a Friend</td></tr> <tr valign="top"><td align="center" valign="top" width="15"></td><td valign="middle">E-mail When Cited</td></tr> <tr valign="top"><td align="center" valign="top" width="15"></td><td valign="middle">E-mail When Letters Appear</td></tr> <tr valign="top"><td colspan="2"></td></tr> </tbody></table> </td> </tr> <tr> <td align="center" bgcolor="#e8e8d1" width="200">
</td> </tr> <tr> <td> <table bgcolor="#ffffff" border="0" cellpadding="2" cellspacing="0" width="100%"> <tbody><tr valign="top"><td colspan="2"></td></tr> <tr valign="top"><td colspan="2"></td></tr> </tbody></table> </td> </tr> </tbody></table> </td></tr></tbody></table> <!-- end of outer content box1 --> <!-- end of outer content box2 --> <!-- TEXT --> <!-- <CENTER> A Clinical Trial of a Whole-Virus H5N1 Vaccine Derived from Cell Culture</CENTER> --> <!-- <CENTER> </NOBR><NOBR>Hartmut J. Ehrlich, M.D.</NOBR>, <NOBR>Markus Müller, M.D.</NOBR>, <NOBR>Helen M.L. Oh, M.D.</NOBR>, <NOBR>Paul A. Tambyah, M.B., B.S.</NOBR>, <NOBR>Christian Joukhadar, M.D.</NOBR>, <NOBR>Emanuele Montomoli, Ph.D.</NOBR>, <NOBR>Dale Fisher, F.R.A.C.P.</NOBR>, <NOBR>Greg Berezuk, M.S.</NOBR>, <NOBR>Sandor Fritsch, Ph.D.</NOBR>, <NOBR>Alexandra Löw-Baselli, Ph.D.</NOBR>, <NOBR>Nina Vartian, Ph.D.</NOBR>, <NOBR>Roman Bobrovsky, Ph.D.</NOBR>, <NOBR>Borislava G. Pavlova, Ph.D.</NOBR>, <NOBR>Eva Maria Pöllabauer, M.D.</NOBR>, <NOBR>Otfried Kistner, Ph.D.</NOBR>, <NOBR>P. Noel Barrett, Ph.D.</NOBR> the Baxter H5N1 Pandemic Influenza Vaccine Clinical Study Team</NOBR> </CENTER> --> ABSTRACT
Background Widespread infections of avian species with avian<sup> </sup>influenza H5N1 virus and its limited spread to humans suggest<sup> </sup>that the virus has the potential to cause a human influenza<sup> </sup>pandemic. An urgent need exists for an H5N1 vaccine that is<sup> </sup>effective against divergent strains of H5N1 virus.<sup> </sup>
Methods In a randomized, dose-escalation, phase 1 and 2 study<sup> </sup>involving six subgroups, we investigated the safety of an H5N1<sup> </sup>whole-virus vaccine produced on Vero cell cultures and determined<sup> </sup>its ability to induce antibodies capable of neutralizing various<sup> </sup>H5N1 strains. In two visits 21 days apart, 275 volunteers between<sup> </sup>the ages of 18 and 45 years received two doses of vaccine that<sup> </sup>each contained 3.75 µg, 7.5 µg, 15 µg, or<sup> </sup>30 µg of hemagglutinin antigen with alum adjuvant or 7.5<sup> </sup>µg or 15 µg of hemagglutinin antigen without adjuvant.<sup> </sup>Serologic analysis was performed at baseline and on days 21<sup> </sup>and 42.<sup> </sup>
Results The vaccine induced a neutralizing immune response not<sup> </sup>only against the clade 1 (A/Vietnam/1203/2004) virus strain<sup> </sup>but also against the clade 2 and 3 strains. The use of adjuvants<sup> </sup>did not improve the antibody response. Maximum responses to<sup> </sup>the vaccine strain were obtained with formulations containing<sup> </sup>7.5 µg and 15 µg of hemagglutinin antigen without<sup> </sup>adjuvant. Mild pain at the injection site (in 9 to 27% of subjects)<sup> </sup>and headache (in 6 to 31% of subjects) were the most common<sup> </sup>adverse events identified for all vaccine formulations.<sup> </sup>
Conclusions A two-dose vaccine regimen of either 7.5 µg<sup> </sup>or 15 µg of hemagglutinin antigen without adjuvant induced<sup> </sup>neutralizing antibodies against diverse H5N1 virus strains in<sup> </sup>a high percentage of subjects, suggesting that this may be a<sup> </sup>useful H5N1 vaccine. (ClinicalTrials.gov number, NCT00349141<!-- HIGHWIRE EXLINK_ID="358:24:2573:1" VALUE="NCT00349141" TYPEGUESS="CLINTRIALGOV" --> [ClinicalTrials.gov] <!-- /HIGHWIRE -->.)<sup> </sup>
<sup> </sup>
<hr>The emergence of a new human influenza pandemic caused by an<sup> </sup>avian virus strain is possible. Vaccination against pandemic<sup> </sup>influenza is considered to be the most effective option to limit<sup> </sup>its spread. However, the conventional approaches to the manufacture<sup> </sup>of influenza vaccines have a number of disadvantages and raise<sup> </sup>concern about whether sufficient quantities of an effective<sup> </sup>vaccine can be made available early enough at the onset of a<sup> </sup>pandemic to have a major effect on public health.<sup>1</sup> In addition,<sup> </sup>clinical studies of conventional split-vaccine formulations<sup> </sup>without adjuvant have shown poor immunogenicity.<sup>2</sup><sup>,</sup><sup>3</sup> It has been<sup> </sup>suggested that whole-virus vaccines have the potential to be<sup> </sup>more immunogenic than split-virus or subunit vaccines in previously<sup> </sup>unvaccinated populations.<sup>4</sup><sup>,</sup><sup>5</sup> The first clinical study of a whole-virus<sup> </sup>vaccine against avian influenza H5N1 virus showed that a substantially<sup> </sup>reduced antigen dosage (10 µg) with an alum formulation<sup> </sup>induced seroconversion in nearly 100% of subjects.<sup>6</sup><sup> </sup> All these studies were carried out with vaccines manufactured<sup> </sup>by conventional methods (i.e., with the use of embryonated chicken<sup> </sup>eggs and modified, attenuated reassortant viruses produced by<sup> </sup>reverse genetics).<sup>7</sup> We have devised a strategy for the development<sup> </sup>of an H5N1 vaccine that involves the use of a wild-type virus<sup> </sup>(i.e., the strain circulating in nature) grown in a Vero cell<sup> </sup>culture. This strategy has the advantage that the lead time<sup> </sup>for pandemic vaccine production can be reduced, since the generation<sup> </sup>of attenuated reassortants is not required, although the requirement<sup> </sup>for the use of enhanced biosafety level 3 (BSL-3) facilities<sup> </sup>for such a strategy is a relative drawback. In addition, cell<sup> </sup>culture provides a robust manufacturing platform that eliminates<sup> </sup>dependence on embryonated chicken eggs, which would be an advantage<sup> </sup>in the event of limited availability of such eggs during a pandemic<sup> </sup>caused by a highly pathogenic avian virus. This technique was<sup> </sup>used to develop a whole-virus vaccine that was highly immunogenic<sup> </sup>in animal models.<sup>8</sup> We report on the safety and immunogenicity<sup> </sup>of this vaccine, using formulations with and without alum adjuvant.
" snip"
and this text from baxter
The New England Journal of Medicine Publishes Study Investigating the Safety and Efficacy of Baxter's Cell-Based Pandemic, Avian Flu Vaccine
<table border="0" cellpadding="0" cellspacing="0" width="649"> </table>
<!-- #BeginEditable "release" --> First scientific, peer-reviewed publication showing the candidate vaccine
induced neutralizing antibodies against widely divergent H5N1 virus
DEERFIELD, Ill., June 11 /PRNewswire-FirstCall/ -- Baxter International
Inc. (NYSE: BAX) announced publication in the June 12, 2008 issue of The
New England Journal of Medicine (NEJM) of data demonstrating Baxter's
candidate avian influenza (H5N1) vaccine, CELVAPAN, met Phase I/II trial
endpoints for safety and immunogenicity (generating a functional immune
response). This is the first peer-reviewed publication of study results for
CELVAPAN, the first cell culture-derived avian influenza vaccine to undergo
clinical evaluation. The primary authors of the manuscript are Hartmut J.
Ehrlich, MD, vice president of global research and development for Baxter's
BioScience business, and Noel Barrett, vice president of Baxter's vaccines
research.
"Cell culture technology could represent the future of influenza
vaccine production," said John Oxford, professor of Virology, The Queen
Mary School of Medicine, London, United Kingdom. "Baxter has demonstrated
the ability to rapidly make large quantities of the vaccine that may
protect people against divergent H5N1 viruses."
Based on manufacturing processes, Vero cell technology may offer
several advantages versus conventional egg-based vaccine technology.
Baxter's Vero cell manufacturing process is more rapid due to its ability
to use a "native" virus that does not need to be modified to allow growth
in chicken eggs, therefore accelerating vaccine production.
"CELVAPAN combines innovative science and breakthrough production
technology with the aim of protecting people against an H5N1 pandemic flu
infection," said Hartmut J. Ehrlich, MD. "This is an immunogenic vaccine
without the need for an adjuvant to boost the immune response."
About CELVAPAN
CELVAPAN is manufactured in a cell culture-based system in Bohumil,
Czech Republic, at one of the largest cell culture vaccine production
facilities in the world. Vero cell technology uses a well-established cell
line originally derived from African green monkey kidneys in 1962. A
continuous cell line has been derived from these cells so that an unlimited
supply of cells is available without the requirement of generating
additional cells from animals.
Baxter's candidate avian flu vaccine is derived from the H5N1 strain
A/Vietnam/1203/2004. Its antigen composition and structure are identical to
the actual virus circulating in nature without the need to enhance an
immune response by including adjuvants, additives that may cause side
effects. In this Phase I/II study, CELVAPAN induced an immune response that
is similar to the body's defense against a natural virus infection. Earlier
this year CELVAPAN was accepted for licensure review by the Committee for
Medicinal Products for Human Use within the European Medicines Agency,
making it the first cell culture-based pandemic influenza vaccine to be
reviewed by the regulatory authority. The U.S. National Institute of
Allergy and Infectious Diseases (NIAID), part of the National Institutes of
Health, is also conducting a trial with Baxter's CELVAPAN in the United
States.
Phase I/II Clinical Trial Results
The randomized Phase I/II study enrolled 284 subjects in Austria and
Singapore (ages 18-45) and met its immunogenicity and safety endpoints. The
study mainly investigated the ability of the vaccine to induce substantial
levels of cross-immunity against divergent H5N1 strains.
The trial tested four different antigen concentrations ranging from
3.75 micrograms to 30 micrograms; 7.5 micrograms and 15 micrograms
formulations were studied with and without adjuvant (additive).
Statistically, the non- adjuvanted formulations induced the highest rates
of subjects with a titer (antibody concentration in the blood) more than
1:20 after the first (40.5 percent and 39.5 percent for 7.5 micrograms and
15 micrograms) and second (76.2 percent and 70.7 percent for 7.5 micrograms
and 15 micrograms) vaccinations, demonstrating this vaccine generates a
robust immune response.
Regarding seroconversion (development of antibodies) or the percent of
subjects demonstrating a more than four-fold increase in titer after
immunization, the highest responses were again seen with the 7.5 micrograms
and 15 micrograms non-adjuvanted formulations, with 69.0 percent and 68.3
percent seroconversion, respectively.
High levels of cross-reactivity were demonstrated against the A/Hong
Kong strain with the 7.5 micrograms and 15 micrograms non-adjuvanted
formulations (76.2 percent and 78.0 percent, respectively, with
neutralizing titer more than 1:20). The responses against the clade 2
strain were somewhat lower (45.2 percent and 36.6 percent with NT titers
greater than or equal to 1:20 for the 7.5 micrograms and 15 micrograms
non-adjuvanted formulations, respectively). This demonstrates the ability
of the vaccine to induce cross-reactive immune responses against divergent
H5N1 strains.
The most common side effects were injection site reactions, headaches
and fatigue, and the most common local reaction was pain at the injection
site.
Baxter's Pre-Pandemic Planning Efforts
Baxter works closely with governments worldwide on pandemic
preparation. The company has delivered several million doses of CELVAPAN to
various governments around the world. In 2006, Baxter entered into a
pandemic preparedness contract with the Austrian Ministry of Health to
supply 16 million doses of pandemic influenza vaccine in the event a
pandemic is declared. The company also delivered a stockpile of two million
doses of CELVAPAN to the U.K. Department of Health as part of an agreement
announced in February 2006. To improve access to treatment in developing
countries, Baxter also supports the World Health Organization's pandemic
planning programs through participation in a planned international
stockpile program.
Baxter is also working with the NIAID in partnership with Fisher
BioServices Inc., and with the U.S. Department of Health and Human Services
in partnership with DynPort Vaccine Company LLC (DVC LLC), a Computer
Science Corporation Company, to further develop Vero cell culture-based
candidate pandemic and seasonal influenza vaccines. Baxter is working with
the U.S. Department of Health and Human Services, in partnership with DVC
LLC, on a seasonal Phase III clinical trial that is currently underway in
the United States and also plans to initiate a pandemic Phase I trial later
this year in the United States with an H5N1 reverse genetic reassorted (RG)
Indonesia strain vaccine. Baxter is also working with the NIAID in
partnership with Fisher BioServices Inc. on a Phase I trial in the United
States using the H5N1 Vietnam strain.
About Pandemic Flu
A pandemic is a global disease outbreak of a virus for which there is
little or no immunity in the human population, causing serious illness and
spreading easily person-to-person worldwide. Most cases of avian flu
infection in humans have resulted from direct or close contact with
infected poultry (e.g., domesticated chicken, ducks, and turkeys) or
surfaces possibly contaminated from feces of infected birds. Avian
influenza infection follows an unusually aggressive clinical course, with
rapid deterioration and high fatality. Primary viral pneumonia and
multi-organ failure have been common among people who have become ill with
avian influenza.
About Baxter
Baxter International Inc., through its subsidiaries, assists healthcare
professionals and their patients with treatment of complex medical
conditions, including hemophilia, immune disorders, cancer, infectious
diseases, kidney disease, trauma and other indications. The company applies
its expertise in medical devices, pharmaceuticals and biotechnology to make
a meaningful difference in patients' lives.
This release includes forward-looking statements concerning the
company's vaccine products, including with respect to clinical trials,
licensures, and the advantages of the vaccine products. The statements are
based on assumptions about many important factors, including the following,
which could cause actual results to differ materially from those in the
forward-looking statements: satisfaction of regulatory and other
requirements for timely commencement of additional clinical trials;
additional clinical results demonstrating the safety and efficacy of the
products; market acceptance of vaccines developed with Vero cell technology
relative to egg-based or other alternatives; continued public commitment to
addressing avian flu and other pandemic threats including additional
experience producing such vaccines at a large scale; and other risks
identified in the company's most recent filing on Form 10-Q and other SEC
filings, all of which are available on the company's web site. The company
does not undertake to update its forward-looking statements.
<!-- begin SiteCatalyst code version: H.4. -->
</pre><table width="649"><script language="JavaScript"> s.server=server() s.channel="news release" s.pageName="news_release_the new england journal of medicine publishes study investigating the safety and efficacy of baxter's cell-based pandemic, avian flu vaccine" s.prop2="104" s.prop3="06-11-2008" /************* DO NOT ALTER ANYTHING BELOW THIS LINE ! **************/ var s_code=s.t();if(s_code)document.write(s_code); //--></script><!-- End SiteCatalyst code version: H.4. --></table> <!--Prn.com 1.5: Added Bottom link icon and text field --><!--Prn.com 1.5: Bottom link icon and text field ends here--> SOURCE Baxter International Inc.
Comment