Re: _|INDONESIA_RUSSIA: VACCINE DEAL?|_
The use of any vaccine has its trade-offs... Use of live virus vaccines need to be evaluated carefully especially for certain patient groups... Here are a few articles I found on the use of live attenuated viruses for influenza...
http://www.continuitycentral.com/news02321.htm
Potential breakthrough in H5N1 vaccine development
University of Pittsburgh researchers have announced that they have genetically engineered an avian flu vaccine from the critical components of the deadly H5N1 virus that completely protected mice and chickens from infection.
Because this vaccine contains a live virus, it may be more immune-activating than avian flu vaccines prepared by traditional methods, say the researchers.
Furthermore, because it is grown in cells, it can be produced much more quickly than traditional vaccines, making it an extremely attractive candidate for preventing the spread of the virus in domestic livestock populations and, potentially, in humans, according to the study, to be published in the February 15 issue of the Journal of Virology and made available early online.
"The results of this animal trial are very promising, not only because our vaccine completely protected animals that otherwise would have died, but also because we found that one form of
the vaccine stimulates several lines of immunity against H5N1," said Andrea Gambotto, M.D., assistant professor in the departments of surgery and molecular genetics and biochemistry, University of Pittsburgh School of Medicine, and lead author of the study.
Dr. Gambotto and his colleagues
constructed the vaccine by genetically engineering a common cold virus, called adenovirus, to express either all or parts of an avian influenza protein called hemagglutinin (HA) on its surface. Found on the surface of all influenza viruses, HA allows the virus to attach to the cell that is being infected and is, therefore, critical to the influenza virus' ability to cause illness and death.
Based on the published sequence of the Vietnam strain of the H5N1 avian influenza virus, members of the University of Pittsburgh Vector Core Facility, led by Wentao Gao, Ph.D., research instructor in the School of Medicine's department of surgery,
constructed several adenovirus "vectors"- viruses that have been modified to serve as a vector, or delivery vehicle, for foreign genes or DNA - containing either the full genetic sequence of the HA protein or sequences for only parts, or subunits, of HA. They also constructed a vector containing sequences for a portion of the HA protein from the H5N1 Hong Kong strain.
Collaborating with investigators Xiuhua Lu, Ph.D., Doan C. Nguyen, M.D., Yumi Matsuoka, Ph.D., Ruben O. Donis, Ph.D., and Jaquelin M. Katz, Ph.D., of the Influenza Branch of the Centers for Disease Control and Prevention, Dr. Gambotto's team tested the ability of their slightly different vaccines to protect mice from infection by wild-type H5N1 by comparing its performance to an adenovirus vector containing no H5N1 genes, or an "empty vector." The investigators then observed the H5NI-exposed mice for any signs of illness, including weight loss and death, and also checked their blood for anti-viral antibodies and other markers of H5N1-specific immunity.
All of the mice immunized with the empty vector vaccine experienced substantial weight loss beginning about three days after exposure to wild-type H5N1, and all were dead within six to nine days of avian flu exposure. In sharp contrast, most of the mice immunized with the adenovirus containing either the whole or part of the HA protein showed only mild and short-lived weight loss and survived H5N1 infection.
When the investigators looked for evidence of a specific immune response to H5N1, they found similar results. Although they were able to isolate high levels of infectious H5N1 from multiple organs in the mice vaccinated with the empty vector, and to various degrees in animals vaccinated with the vectors containing the HA subunits, they isolated only very small amounts of H5N1 from the mice immunized with the full-length HA vaccine three days after infection. Six days after infection, they could not detect any infectious H5N1 in the organs of mice immunized with the full-length HA vaccine.
Moreover, when they looked at the cellular immune response to vaccination, they found that all of the animals immunized with full-length HA or the subunit vaccines developed strong cellular immune responses. However, only the full-length HA-immunized mice developed strong T-cell responses to both of the HA subunits. According to Simon Barratt-Boyes, B.V.Sc., Ph.D., associate professor, department of infectious diseases and microbiology, University of Pittsburgh Graduate School of Public Health, and one of the co-authors of the study,
the ability of this particular recombinant vaccine - a vaccine carrying only the important immune-stimulating proteins - to induce both antibody- and T cell-directed immunity is extremely encouraging.
"This means that this recombinant vaccine can stimulate several lines of defense against the H5N1 virus, giving it greater therapeutic value. More importantly, it suggests that even if H5N1 mutates, the vaccine is still likely to be effective against it. How effective, we are not sure," Dr. Barratt-Boyes cautioned. "We won't know until that occurs."
Based on the superior degree of protection that they found in mice vaccinated with full-length HA vaccine, Dr. Gambotto's group, working with David E. Swayne, D.V.M., Ph.D., at the U.S. Department of Agriculture, tested its effectiveness in chickens, which have almost a 100 percent mortality rate to H5N1 exposure. In all, the researchers inoculated four groups of chickens either through their noses (intranasally) or with subcutaneous injections of either the HA-containing vaccine or the empty vector vaccine. The chickens were then challenged with a dose of whole H5N1 virus 10,000 times greater than the dose given to the mice and significantly greater than the dose farm chickens are likely to be exposed to during a natural outbreak.
Interestingly, all of the chickens that were immunized subcutaneously survived exposure to H5N1, developed strong HA-specific antibody responses and showed no clinical signs of disease. In contrast, half of the chickens immunized intranasally died and half survived. All of the chickens immunized with the empty vector (intranasally and subcutaneously) died within two days of H5N1 exposure.
The researchers are still not yet sure why the subcutaneous delivery is more effective than the intranasal delivery of the vaccine, but they suggested it may be because the adenovirus vector they used has limited infectivity via the nose and respiratory tract.
Dr. Gambotto and his colleagues suggest that rather than replacing traditional inactivated influenza vaccines, their adenovirus-based vaccine could be a critically important complement to them. Because it appears to be so successful in immunizing chickens against H5N1, widespread inoculation of susceptible poultry populations could provide a significant barrier to the spread of the virus via that route in this country and other countries that have so far been spared from avian flu. Also, if there were a disruption in the traditional vaccine production pipeline, a recombinant vaccine could be an attractive alternative for human immunization as well, they said.
Indeed, according to Dr. Gambotto, there are several major advantages to this type of vaccine development approach over traditional approaches. Flu vaccines currently are prepared in fertilized chicken eggs, a process developed more than 50 years ago that requires millions of fertilized eggs that would be in short supply if a pandemic were to occur. The recombinant vaccine approach grows the vaccine in cell cultures, which are unlimited in supply. Another major advantage of this approach is its speed.
"
It takes a little over a month for us to develop a recombinant vector vaccine compared to a minimum of several months via traditional methods," he explained. "This capacity will be particularly invaluable if the virus begins to mutate rapidly, a phenomenon that often limits the ability of traditional vaccines to contain outbreaks of mutant strains." Dr. Gambotto added that his group is planning a small clinical trial of the vaccine in humans in the very near future.
The research was supported by internal University of Pittsburgh funds. Others involved in this study include Paul D. Robins, Ph.D. and Angela Montecalvo, Ph.D., University of Pittsburgh School of Medicine; and Adam C. Soloff, B.S., University of Pittsburgh Graduate School of Public Health.
http://medicine.plosjournals.org/perlserv?request=get-document&doi=10.1371/journal.pmed.0030360
Live, Attenuated Influenza A H5N1 Candidate Vaccines Provide Broad Cross-Protection in Mice and Ferrets
Amorsolo L. Suguitan Jr.1, Josephine McAuliffe1, Kimberly L. Mills1, Hong Jin2, Greg Duke2, Bin Lu2, Catherine J. Luke1, Brian Murphy1, David E. Swayne3, George Kemble2, Kanta Subbarao1*
1 Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America, 2 MedImmune Vaccines, Mountain View, California, United States of America, 3 Southeast Poultry Research Laboratory, Agricultural Research Service, United States Department of Agriculture, Athens, Georgia, United States of America
Background
Recent outbreaks of highly pathogenic influenza A H5N1 viruses in humans and avian species that began in Asia and have spread to other continents underscore an urgent need to develop vaccines that would protect the human population in the event of a pandemic.
Methods and Findings
Live, attenuated candidate vaccines possessing genes encoding a modified H5 hemagglutinin (HA) and a wild-type (wt) N1 neuraminidase from influenza A H5N1 viruses isolated in Hong Kong and Vietnam in 1997, 2003, and 2004, and remaining gene segments derived from the cold-adapted (ca) influenza A vaccine donor strain, influenza A/Ann Arbor/6/60 ca (H2N2), were generated by reverse genetics. The H5N1 ca vaccine viruses required trypsin for efficient growth in vitro, as predicted by the modification engineered in the gene encoding the HA, and possessed the temperature-sensitive and attenuation phenotypes specified by the internal protein genes of the ca vaccine donor strain. More importantly, the candidate vaccines were immunogenic in mice.
Four weeks after receiving a single dose of 106 50% tissue culture infectious doses of intranasally administered vaccines, mice were fully protected from lethality following challenge with homologous and antigenically distinct heterologous wt H5N1 viruses from different genetic sublineages (clades 1, 2, and 3) that were isolated in Asia between 1997 and 2005. Four weeks after receiving two doses of the vaccines, mice and ferrets were fully protected against pulmonary replication of homologous and heterologous wt H5N1 viruses.
Conclusions
The promising findings in these preclinical studies of safety, immunogenicity, and efficacy of the H5N1 ca vaccines against antigenically diverse H5N1 vaccines provide support for their careful evaluation in Phase 1 clinical trials in humans.
Funding: This research was supported in part by the Intramural Research Program of the NIH, NIAID. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
Academic Editor: Joseph S. M. Peiris, The University of Hong Kong, China
Citation: Suguitan Jr. AL, McAuliffe J, Mills KL, Jin H, Duke G, et al. (2006) Live, Attenuated Influenza A H5N1 Candidate Vaccines Provide Broad Cross-Protection in Mice and Ferrets. PLoS Med 3(9): e360 doi:10.1371/journal.pmed.0030360
Received: April 25, 2006; Accepted: August 1, 2006; Published: September 12, 2006
http://content.nejm.org/cgi/content/full/356/7/685
New England Journal of Medicine Volume 356:685-696 February 15, 2007 Number 7
Live Attenuated versus Inactivated Influenza Vaccine in Infants and Young Children
Robert B. Belshe, M.D., Kathryn M. Edwards, M.D., Timo Vesikari, M.D., Steven V. Black, M.D., Robert E. Walker, M.D., Micki Hultquist, M.S., George Kemble, Ph.D., Edward M. Connor, M.D., for the CAIV-T Comparative Efficacy Study Group
ABSTRACT
Background Universal vaccination of children 6 to 59 months of age with trivalent inactivated influenza vaccine has recently been recommended by U.S. advisory bodies. To evaluate alternative vaccine approaches,
we compared the safety and efficacy of intranasally administered live attenuated influenza vaccine with those of inactivated vaccine in infants and young children.
Methods Children 6 to 59 months of age, without a recent episode of wheezing illness or severe asthma, were randomly assigned in a 1:1 ratio to receive either cold-adapted trivalent live attenuated influenza vaccine (a refrigeration-stable formulation of live attenuated intranasally administered influenza vaccine) or trivalent inactivated vaccine in a double-blind manner. Influenza-like illness was monitored with cultures throughout the 2004?2005 influenza season.
Results Safety data were available for 8352 children, and 7852 children completed the study according to the protocol.
There were 54.9% fewer cases of cultured-confirmed influenza in the group that received live attenuated vaccine than in the group that received inactivated vaccine (153 vs. 338 cases, P<0.001).
The superior efficacy of live attenuated vaccine, as compared with inactivated vaccine, was observed for both antigenically well-matched and drifted viruses. Among previously unvaccinated children, wheezing within 42 days after the administration of dose 1 was more common with live attenuated vaccine than with inactivated vaccine, primarily among children 6 to 11 months of age; in this age group, 12 more episodes of wheezing were noted within 42 days after receipt of dose 1 among recipients of live attenuated vaccine (3.8%) than among recipients of inactivated vaccine (2.1%, P=0.076). Rates of hospitalization for any cause during the 180 days after vaccination were higher among the recipients of live attenuated vaccine who were 6 to 11 months of age (6.1%) than among the recipients of inactivated vaccine in this age group (2.6%, P=0.002).
Conclusions Among young children, live attenuated vaccine had significantly better efficacy than inactivated vaccine. An evaluation of the risks and benefits indicates that live attenuated vaccine should be a highly effective, safe vaccine for children 12 to 59 months of age who do not have a history of asthma or wheezing. (ClinicalTrials.gov number, NCT00128167 [ClinicalTrials.gov] .)
Discussion
Many believe that the successful control of annual influenza epidemics depends on vaccinating a high proportion of children.16,17,18 As U.S. public health authorities move toward this goal, highly effective vaccines are needed, including vaccines with efficacy against antigenically drifted influenza strains. The live attenuated influenza vaccine we used has many of the characteristics that are desirable for the control of epidemic influenza. In addition to its high acceptability because of the mode of administration, the significantly higher efficacy of this live attenuated vaccine than of the licensed inactivated vaccine suggests that it can play an important role in the control of influenza. This higher efficacy was seen not only for well-matched strains but also for viruses that were antigenically drifted from the antigen in the vaccine.
Some earlier studies have suggested the potential for wheezing in young children after receipt of live attenuated influenza vaccine,15 whereas others have not.10,16 Our comprehensive, prospective safety study showed an increased risk of medically significant wheezing (within 42 days after vaccination) among recipients of live attenuated vaccine who were younger than 12 months of age. The pathogenesis of wheezing in some children given live attenuated vaccine remains unknown, although in our study, the wheezing developed after the peak of viral replication and at the time when immune responses to the viruses are expected ? that is, during weeks 2, 3, and 4 after vaccination.
The incidence of serious adverse events did not differ significantly between the two groups. However, in post hoc analyses, rates of hospitalization for any cause among infants 6 to 11 months of age were significantly higher in the live-attenuated-vaccine group than in the inactivated-vaccine group. In addition, higher, but not significantly higher, rates of hospitalization were observed among children in the age groups of 12 to 23 months, 24 to 35 months, and 36 to 47 months who had a history of wheezing illness before entering the study. These observations require further study. Children 12 months of age or older who had no history of wheezing illness before vaccination and who received live attenuated vaccine had lower rates of hospitalization for any cause during the study than those who received inactivated vaccine. On the basis of our results, the risk?benefit ratio for live attenuated vaccine appears favorable among children 12 to 47 months of age who have no history of wheezing.
Until additional data are available, the observations related to medically significant wheezing and rates of hospitalization will restrict the use of live attenuated vaccine in children younger than 1 year and in children 12 to 47 months of age who have a history of asthma or wheezing. Additional studies to determine the optimal use of both vaccines in infants and young children are warranted.
The high influenza attack rate among children in the inactivated-vaccine group who were less than 12 months of age and had a history of wheezing (14%) suggests that inactivated vaccine has low efficacy in this group. Further studies might show whether an initial dose of inactivated vaccine followed by live attenuated vaccine would provide optimal protection for children younger than 1 year of age while also ensuring maximum vaccine safety.
http://www.journals.uchicago.edu/doi/abs/10.1086/315246
The Journal of Infectious Diseases 2000;181:725?728
? 2000 by the Infectious Diseases Society of America. All rights reserved.
0022-1899/2000/18102-0044$02.00
CONCISE COMMUNICATION
Comparison of the Safety, Vaccine Virus Shedding, and Immunogenicity of Influenza Virus Vaccine, Trivalent, Types A and B, Live Cold-Adapted, Administered to Human Immunodeficiency Virus (HIV)-Infected and Non-HIV-Infected Adults
James C. King, Jr.,1 John Treanor,4 Patricia E. Fast,5 Mark Wolff,2 Lihan Yan,2 Dominic Iacuzio,3,a Bernard Readmond,1 Diane O'Brien,4 Kenneth Mallon,5 William E. Highsmith,1 John S. Lambert,1 and Robert B. Belshe6
1University of Maryland Medical Center, Baltimore, 2EMMES Corp., Potomac, and 3National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland; 4University of Rochester Medical Center, Rochester, New York; 5Aviron, Mountain View, California; 6Saint Louis University School of Medicine, St. Louis, Missouri
Fifty-seven human immunodeficiency virus (HIV)-infected (CDC class A1-2) and 54 non-HIV-infected adults, not prescreened for influenza susceptibility, were randomized to receive trivalent live attenuated influenza vaccine (LAIV) or placebo intranasally. LAIV was safe and well tolerated with no serious adverse events attributable to vaccine. Reactogenicity rates were similar in LAIV and placebo recipients except that runny nose/nasal congestion was significantly more common in LAIV recipients regardless of HIV status. No prolonged shedding of LAIV was observed in HIV-infected participants. HIV RNA levels were not increased and CD4 counts were not decreased in HIV-infected LAIV recipients compared with placebo recipients after immunization.
Shedding of LAIV and increases in antibody titers were infrequent, consistent with prior experience in unscreened adults. The data suggest that inadvertent vaccination with LAIV in relatively asymptomatic HIV-infected adults would not be associated with frequent significant adverse events.
Received 14 June 1999; revised 24 September 1999; electronically published 8 February 2000.
Written informed consent was obtained from all study subjects. Human experimentation guidelines of the US Department of Health and Human Services and of each institution (University of Maryland at Baltimore, University of Rochester) were followed during this research study.
oly(C<tinf>12</tinf>U) (Ampligen) as an adjuvant. At 14 days after the final inoculation, the inoculated mice were challenged with either the A/HongKong/483/97, the A/Vietnam/1194/04, or the A/Indonesia/6/05 strain of H5N1 influenza virus.
