Advisory committee on immunization practices




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Preliminary Considerations for U.S. H.P.V. Vaccine Recommendations
Presenter: Dr. Lauri Markowitz, N.C.H.S.T.P.


Overview: Vaccine licensure/production assumptions; disease burden and epidemiology; vaccine acceptability; programmatic issues; vaccine impact/C.E.; potential recommendation strategies


The H.P.V. Working Group has met several times over the 18 months. The current assumptions made by the Working Group include: 1) the mid-2006 licensure of quadrivalent H.P.V. 6,11,16,18 vaccine for use in females aged 9 to 26 years; its potential later licensure for use in males; and still later, licensure of a bivalent H.P.V. 16,18 vaccine for use in females.


The data presented at this meeting showed the vaccine’s efficacy and safety, with local reactions as the primary side effect. Immunogenicity was well demonstrated by very high seroconversion rates in those aged 9 to 26 years. The vaccine’s G.M.T.s exceeded those after natural infection and were highest in those vaccinated at younger ages; its level of immunity also exceeded that of natural infection, even with a plateau at 18 months post-vaccination. The duration of protection and need for a booster dose remain unknown and there is no known serologic correlate of protection.

The burden of H.P.V.-related disease was presented at the June 2005 A.C.I.P. meeting. Cervical cancer cases and deaths in the United States during 2005 are estimated to be greater than 10,000 and 3700, respectively, aside from other H.P.V.-caused conditions requiring medical attention. An estimated greater than 50 percent of sexually active adults will have H.P.V. at some point, most being asymptomatic and naturally resolving. Data indicate that H.P.V. is acquired soon after sexual debut, 39 percent within 24 months of first sex. Vaginal sexual activity among U.S. females has been estimated at 26 percent by age 15 and 77 percent by age 19.


Vaccine acceptability. Vaccines targeting control of S.T.D.s have the potential to raise social concerns, but education about H.P.V. and H.P.V. vaccine may lead to increased acceptability. Providers and parents appear to be more likely to accept vaccination of older adolescents.


Programmatic issues include accommodation of H.P.V. vaccination in the ever expanding list of priorities for the 11 to 12 year-old preadolescent healthcare visit. Studies of vaccine impact and cost effectiveness are published and ongoing, and will be presented at the next A.C.I.P. meeting. The economic analyses to date have estimated a cost of approximately 300 dollars for three doses, including administration cost. Recommendations for vaccine use must take into account several Potential strategies, including recommendations for routine use, catch-up, or permissive recommendations. The current H.P.V. vaccines will not eliminate the need for cervical cancer screening, since types other than H.P.V. 16 and -18 cause approximately 30 percent cervical cancer. This was a basic assumption in the models developed to evaluate H.P.V. vaccine’s expected impact.


Strategies discussed for routine recommendation included several considerations. Vaccination of early adolescents aged 11 to 12 years (or younger) would allow vaccination before sexual debut for a larger number of persons. The data indicate higher antibody titers at this age, which also fits the current adolescent immunization schedule. Vaccination of older adolescents may provide better protection in the high-risk years, if there is waning immunity (which is unknown) , without requiring a booster. There also may be less social resistance to a recommendation for vaccination at this age, and therefore higher coverage.


At the A.C.I.P. meeting to be held in February 2006 the Working Group will present analytical data on vaccination C.E. and impact, presuming further information data from G.S.K. and Merck. Preliminary recommendations can be discussed then and in June, and perhaps a vote on the quadrivalent H.P.V. vaccine can be taken at the A.C.I.P. meeting to be held in June 2006. Subsequent meeting topics will include discussion of the use of H.P.V. vaccine in males, and a bivalent H.P.V. vaccine. In the meantime, the N.C.H.S.T.P. Website has information on H.P.V. disease and cervical cancer, at www.cdc.gov/std/hpv/, for women, patients and healthcare providers. The site also links to the American Cancer Society and the National Cancer Institute.


Discussion:

  • Dr. Mark Feinburg (Merck) reported their building of production facilities which have been operating for the last two years. Merck expects to have no problem supplying H.P.V. vaccine for the populations studied.

  • Dr. Katz commented on the survey of practitioners at 21 years post-graduation. Given that greater than 66 percent of young pediatricians today are female, the data might be more accurate if they are surveyed. And, to overcome social discomfort with S.T.D.s, he also urged that this vaccine be promoted as a cancer prevention vaccine rather than one for prevention of S.T.D.s.

  • Pediatricians’ reluctance stemming from expected parental objections may not be warranted. Research in general and by Merck on this H.P.V. vaccine in particular indicate that parents rely on and will be influenced by the advice of the pediatrician, and that they will accept the vaccine when they understand the outcomes of H.P.V. infection. Pediatricians could be further educated to these facts. Dr. Murphy added that many parents already have H.P.V. and do not want their children to be infected.

  • The two imminent H.P.V. vaccines differ in that Merck’s quadrivalent vaccine includes the two genotypes that cause genital warts, and so targets males and females, while G.S.K.’s bivalent vaccine targets only cervical cancer in women. The Working Group is focusing on developing proposed recommendations for the vaccine that will be licensed early in 2006.

  • The Working Group has not formally communicated with ENT physicians to determine their attitude to H.P.V., in view of the patients they treat for laryngeal papillomatosis due to H.P.V. 6 and -11. But Dr. Markowitz reported great interest on the part of N.C.I.D. researchers who are working on recurrent respiratory papillomatosis (RRP) with a network of ENT specialists.

  • Dr. Eliav Barr, of Merck, commented that H.P.V. 6 and -11 cause the precancerous dysplasia C.I.N. lesions that are histopathologically indistinguishable from the higher risk H.P.V. types. Eliminating those types will also reduce the “noise in the system.” Merck has also had preliminary inquiries from the RRP network. They plan to evaluate that issue, and expect that the high V.E. for H.P.V. 6 and -11 will also benefit those with RRP.


REVISION TO THE 2002 A.C.I.P. GENERAL RECOMMENDATIONS

Presenter: Dr. Andrew Kroger, N.I.P.


The General Recommendations Workgroup met by teleconference 11 times in 2004 to update the A.C.I.P. General Recommendations document. The updated draft is expected to be presented at the February meeting and be published by the M.M.W.R. in summer of 2006. The revised sections on vaccine administration and storage/handling of immunobiologics have already been presented to A.C.I.P. On this day, the draft section on altered immunocompetence was outlined, which was expanded to include the 2002 document’s section on hematopoetic stem cell transplants. Discussion of the timing and spacing of immunobiologics, which was scheduled for this meeting, was deferred to February.

Changes made to the altered immunocompetence text included:

  • Recommendation that providers order lab tests to assess altered immunocompetence. Several tools are suggested: 1) for humoral immunity, immunoglobulin and I.g. subsets, specific antibody levels, antibodies for tetanus, diphtheria, and pneumococcal vaccine; 2) for cellular immunity, lymphocyte numbers, complete blood count with differential, and lymphocyte subset concentrations and proportions (to determine B-cell deficiency versus T-cell deficiency and then to subset T-cells for CD4+ versus CD8+); and 3) lymphocyte proliferation assays, to measure T-cell proliferation in response to specific or nonspecific stimuli. Finally, since not all laboratory tests are available to all immunization providers, text is added to encourage “consultation with an infectious disease or an allergy/immunology specialist."

  • Added a new section on vaccine indications for people with altered immunocompetence (that is, safety of use of vaccines in general and live vaccines in particular). This is a new section, but the information comes from vaccine-specific A.C.I.P. statements’ recommendations for people with altered immunocompetence.

  • Provides a permissive recommendation to use varicella vaccine and pneumococcal conjugate vaccine following hematopoetic stem cell transplantation, which provides guidance on which restorative vaccines should be given. This references the 2000 document co-authored by C.D.C., the IDSA and the American Society for Blood and Marrow Transplantation, which does not recommend revaccination with varicella or pneumococcal conjugate vaccine. While noting the lack of evidence to recommend varicella and pneumococcal conjugate, there is an acknowledged substantial risk from infection with varicella and Streptococcus pneumoniae during the post-transplant process; this risk is addressed though a permissive recommendation for the use of these two vaccines, based on the physician’s assessment of the patient’s immune status and risk of infection.

  • Provides an option to revaccinate after immune ablation from chemotherapy following acute lymphoblastic leukemia. The text says: "People vaccinated prior to chemotherapy for leukemia, lymphoma, or other malignancies generally are thought to retain immune memory following treatment although revaccination following chemotherapy for acute lymphoblastic leukemia may be indicated." This was based on only one 2005 paper in the Journal of Pediatrics by Brodtman, but the evidence was found to be strong.

  • Cautions against the use of live vaccines in patients on long-term therapy using therapeutic monoclonal antibodies such as tumor necrosis alpha inhibitors and other isoantibodies. It cites the anti-tumor necrosis factor agents adalimumab, infliximab, and etanercept, which can reactivate latent TB infection and disease and also predispose the patient to other opportunistic infections. It also notes the unknown safety and efficacy of concurrent vaccination of live attenuated vaccines with recombinant human immune mediators and immune modulators. Interferons and immune modulators used as therapeutics, such as Lavamisol and BCG, are cited as examples.

  • Inserted a table of contraindications, vaccine effectiveness, and vaccine indications for specific categories of primary and secondary immunodeficiency, and other disease conditions that confer altered immunocompetence. This is a combination of the A.A.P.’s 2003 Red Book recommendations and the A.C.I.P. 1993 table on immunization of individuals with altered immunocompetence. It is indexed in grouped disease conditions according to primary (humoral or cellular) or secondary immunodeficiency conditions, and mostly defines contraindications according to general classes of vaccines. Comments on disease category and vaccine efficacy will be added as will specific vaccines; and indications.


Discussion:

  • After further research, the document will be clarified as to the extent of revaccination being advised after chemotherapy.

  • Dr. Abramson suggested further review of the vaccines listed for primary humoral and complement deficiencies. He also expressed concern about including live attenuated influenza virus with all live viruses, since it cannot replicate in cold temperatures, and this could further discourage uptake. Further, he asked for a time designation for safety (for example, ≥1 year) to the statement advising varicella vaccination for bone marrow transplant patients.

  • Ms. Sandra Jo Hammer, of the California immunization program, suggested that this level of discussion of complex issues affecting only a minimal number of patients might make the General Recommendations less user-friendly, and perhaps should be published elsewhere and referenced. Dr. Kroger responded that the concept of inserting the content of the 1993 Altered Immunocompetence A.C.I.P. document into the 2006 General Recommendations document were strongly encouraged by A.C.I.P. at the February 2005 meeting. It greatly parallels the content of the 2002 document, which also condensed part of the 1993 information.


A vote was deferred to the February 2006 presentation.


HERPES ZOSTER VACCINE

Presenter: Dr. Kenneth Schmader, MD, Duke University/Durham VA Medical Center


Overview: Epidemiology of herpes zoster and post-herpetic neuralgia; risk factors; disease impact in older adults


Herpes zoster is principally a disease of the elderly. Incidence among older adults (age greater than 60 years) ranges from 7.2 to 11.8 cases per 1000 person-years. Retrospective studies estimate U.S. annual incidence at 500,000 to 1 million cases. The zoster vaccine’s Shingles Prevention Study prospectively surveyed people monthly and reported an incidence of 11.1 per 1000 person-years.


Epidemiology. Zoster’s two major risk factors are aging and suppression of cellular immunity. While the lifetime zoster risk is approximately 20 percent, it is approximately 50 percent in those living to age 85. And, although the risk of recurrent herpes zoster is low (1.7 percent to 5.2 percent) in the immunocompetent host, rates are highest among immunocompetent older adults compared to immunocompromised individuals. The zoster rate is also high in all age groups among those with H.I.V./AIDS, lymphoproliferative cancers, immunologic malignancies, lymphomas, organ transplant recipients, lupus patients, and those receiving immunosuppressive treatment. Data charted from the Hope-Simpson study (Proc R Soc Med 1965;58:9-20) dramatically illustrated increased zoster incidence with increasing age, beginning at 60 to 65. Why the risk is higher in females is unclear (studies have conflicting results); blacks have lower risk than whites; and some data indicate a doubled risk for zoster with psychological stress and, some believe, physical trauma.


Morbidity. Zoster morbidity is significant, imposing acute pain in elderly patients. Pain burden data from the Katz and Dworkin et al study (Clin Infect Dis. 2004;39:342-348) measured pain intensity by duration linked to physical roles and social and emotional functioning. About 72 percent of the patients were aged greater than 50 years. Increased pain burden was paralleled by increased pain intensity and duration, described by 42 percent of patients as horrible or excruciating.


Lydick et al (Qual Life Res 1995;4:41-45) measured the devastation to zoster patients’ quality of life by comparing their mean SF-35 (quality of life) scores to those of hypertension, congestive heart failure, diabetes, myocardial infarction, and depression. Two weeks after zoster rash onset, zoster scores often exceeded those of the other serious conditions.


Postherpetic neuralgia (P.H.N.) has no consensus definition. Its diagnosis differs according to the time after rash onset (the literature ranges from 30 to 180 days) and pain intensity (any pain to clinically meaningful pain). Most recent definitions factor pain 90 to 120 days after rash onset. The Bennett study (Hosp Prac. 1998;33:95-98;101-104;107-110) compared and charted neuropathic pain in the U.S. Significantly, the incidence of only two conditions -- low back pain and painful diabetic neuropathy -- exceeded that of P.H.N. As the two most common pain states, the last two are intensively researched, but incidence data remain sparse.


Dworkin and Schmader (Herpes Zoster and Postherpetic Neuralgia, 2nd ed., 2001) charted the proportion of zoster patients aged greater than 50 years, who were given antivirals in the major antiviral trials within 72 hours of rash onset (something that occurs in clinical practice only approximately 50 percent of the time). The data demonstrated some efficacy of antivirals to reduce acute pain and pain duration; however, a substantial proportion (approximately 30 percent) still have P.H.N.


Risk factors. The most important risk factor by far is increasing age. The duration of pain in the elderly is worse: what lasts a month or less in younger groups (for example, 0 to 39) can go on for years among the elderly. Age ≥60 years with severe acute pain and severe rash and prodrome plus rash, carries a positive predictive value of 47 percent for P.H.N. In the absence of these risk factors, the negative predictive value is 88 percent.


Data from Whitley et al (J Infec Dis. 1999;179:9-15) were charted of zoster in adults aged greater than 50 years, with severe, incapacitating pain and an extensive rash ( greater than 47 lesions), versus those who had no or mild acute pain and a less extensive rash. The former group had a approximately 75 percent likelihood of pain remaining at six months after rash onset.


Common complications of zoster include P.H.N., ocular complications of ophthalmic zoster, scarring, and bacterial superinfection. Even those complications that are uncommon are not rare. Particularly among immunosuppressed patients, the following can emerge: cutaneous dissemination, herpes gangrenosum, pneumonitis, hepatitis, encephalitis, motor neuropathies, myelitis, and hemiparesis (granulomatous C.N.S. vasculitis). In particular, motor neuropathies are more common than had been thought. The virus can often transfer from the dorsal horn to the ventral horn and causes painful Bell's palsy, a paralytic limb, or weakness in the thoracic or abdominal musculature.


Ophthalmic zoster is also an important contributor to disease burden, as approximately 15 percent of cases involve the ophthalmic division of the trigeminal nerve. Without antiviral therapy, 50 percent to 70 percent of patients with H.Z.O. develop ocular complications that can proceed even to blindness. The pain has been compared to an ice pick stabbing behind the eye.


Quality of life is dramatically affected in the zoster patient’s physical, psychological, social, and functional life, because they experience many different types of pain. It begins as a spontaneous, constant aching or burning and proceeds to the kind of intermittent shock-like pain that can bring individuals to their knees. Many P.H.N. patients have allodynia, pain prompted by even such gentle stimuli as a breeze or the touch of a soft cloth. The fatiguing pain brings on weight loss and sleep deprivation, lack of physical activity, depression, and isolation.


The basic activities of daily living are significantly impaired. A Liverpool pain clinic study determined that 59 percent of P.H.N. patients could not pursue their usual activities for up to 16 years, with the average being 1.4 years. The Mauskopf et al (Quality Life Res 1994;3:431-435) and Coplan et al (J Pain 2004; 5:344-356) studies confirmed the drastic effect of P.H.N. on the elderly with multiple co-morbidities, and confirmed the strong association between pain severity and duration with interference in living their normal life.


Hospitalizations/economic impact. Three studies were cited1 that demonstrated the increase of zoster hospitalization rates with age. In the C.D.C.-funded Lin study, the mean hospitalization costs over a ten-year period were 12,834 dollars per patient. By 1995, a decade ago, the cost had risen to 16,000 dollars. In approximately 40 percent of the hospitalization studies, the primary cause was herpes zoster, and it was a secondary diagnosis in the remainder. In the Lin study, approximately 30 percent were immunosuppressed; the balance was mostly older immunocompetent adults. The mean length of stay in the MacIntyre study in Australia was 12 days, and approximately 11 in the Lin study.


There was no discussion following this presentation.


INFLUENZA


Vaccine Supply

Presenter: Dr. Greg Wallace, N.I.P.


Overview: Projected 2005-2006 influenza season vaccine distribution, compared to past representative years


A line graph of the cumulative influenza vaccine distribution for 2000, 2002, 2004-05, and 2005-06 was presented. This season’s August/September dose numbers were accurate, and reflected greater than 80 million doses already distributed. The doses for October through January were projections of vaccine that could be obtained if needed. The data presented clearly demonstrated the greater quantities available for this year than at any time since 2000. However, there still could be spot shortages depending upon which supplier is selected.


Discussion:

  • A.C.I.P. members were assured that there should be no shortage of supply for the pediatric vaccine formulations (2.5cc dose) for those aged 6 to 23 months of age. That vaccine, and FluMist,® have less demand than supply this year. Dr. Kathy Coelingh reported that FluMist® distribution data were not yet available, but MedImmune’s orders were higher than last year.

  • There is no way to determine how many doses were unused last year; only distribution data are available.

  • As of October 23, there were no restrictions for vaccination.


Influenza Resistance to Antiviral Drugs

Presenter: Dr. Alexander Klimov, N.C.I.D.


Two classes of drugs are available for influenza prophylaxis and/or treatment: the adamantanes (amantadine and rimantadine, for influenza A only) and neuraminidase inhibitors (oseltamavir and zanamivir). C.D.C. tested for resistance more than 6500 human influenza A (H3N2) viruses that were collected globally from 1994-2005 (Bright et al, 2005: Lancet 366; 1175-1181):


Adamantanes

  • H3N2 resistance to antiviral drugs: In some areas of Asia, such as China and Hong Kong, resistance to the adamantanes exceeds 70 percent; in others (for example, . Singapore, South Korea), it is lower but still significant (35 percent to 45 percent), and is 12 percent in the U.S. Of H3N2 viruses tested at C.D.C., , most (88 percent) have developed resistance since 2003.

  • H1N1 resistance. Three of 678 influenza H1N1 or H1N2 viruses were shown to be resistant

  • Avian H5N1 virus resistance: Based on sequencing data available, 17 of 19 (89 percent) H5N1 viruses isolated from humans were resistant. Resistance in H5N1 isolates from birds is 58 percent (119 of 206 isolates)


Neuraminidase inhibitors. C.D.C. has found no resistance to N.I.s in 1444 H3N2 samples isolated in 2004-2005. Two of 164 H1N1 samples tested in 2004-2005 were resistant, but neither had the mutations known for previously characterized N.I.-resistant strains. For the B strain, one of 304 samples in 2004 and three of 1224 samples in 2005 were resistant. One virus contained mutations in the neuraminidase genes, which previously has been associated with resistant neuraminidase inhibitors.

  • Oseltamivir. Use of oseltamivir has dramatically increased in Japan. Resistance to date is rare: 0.4 percent in adults, but rising to approximately 4 percent in children and up to 18 percent in very young children (6 to 18 months)

  • Zanamivir: No resistance to date has been seen among immunocompetent individuals, but one B virus was isolated from an immunocompromised person.


H5N1 resistance has been tested in 97 isolates from both humans and birds. All of both were still sensitive to both N.I.s. One strain, A/Vietnam/30408/2005/H5N1, which came from a Vietnamese child treated with oseltamivir, had a mix of , resistant and sensitive virus. However, the sensitivity of the virus to oseltamivir was only slightly increased


Conclusion: An alarming increase in the proportion of adamantane-resistant influenza A(H3N2) viruses has occurred over the past several years, but the proportion of human influenza viruses resistant to neuraminidase inhibitors is low. Continued surveillance to track the emergence and spread of drug-resistant viruses will continue.


Discussion:

  • There has been no evidence to date of relapse or treatment failure among immunocompetent individuals who developed the resistant viruses.

  • There are geographic differences in N2 resistance and the frequency of resistance to H5N1. Two genetic clades are circulating in Asia. Human cases in 2003-2005 in Vietnam and Thailand were caused by Clade 1 viruses, while the new cases in Indonesia were caused by viruses from Clade 2. All known H5N1 viruses from clade 1t have the mutation at position 31 of the M2 gene that is typical for viruses resistant to adamantanes. Most of Clade 2 isolates are sensitive to adamnatanes, although not all of them.

  • Because only one case of resistance to oseltamivir has been seen, and was borderline, nothing can yet be definitively said about the correlation between pathogenicity and resistance to neuraminidase inhibitors.


AVIAN INFLUENZA H5N1


Update on H5N1

Presenter: Dr. Nancy Cox, N.C.I.D., Chief, Influenza Branch


Enhanced surveillance of avian influenza H5N1 in Asia by HHS/C.D.C. is ongoing through bilateral agreements with 11 Asian countries and one W.H.O. Regional Office. In the future, surveillance will be expanded into rural areas and additional geographic areas. HHS is supporting the W.H.O.’s Western Pacific Regional Office (WPRO). C.D.C. is strengthening its emerging infectious diseases program in Thailand and is supporting work in Cairo and Jakarta. Those networks have resulted in a large number of H5N1 samples for analysis. W.H.O.’s animal/human interface influenza network is being enhanced, as are communications between public health and veterinary agencies. C.D.C. is supporting the shipment of isolates and specimens.


Maps detailed the location of the national influenza centers, W.H.O. collaborating centers, surveillance sites, nations with bilateral agreements, avian outbreaks and human cases. Migrating birds spread the infection to Russian, Mongolia and Kazakhstan. An infected bird imported to the U.K. was quarantined, and H5N1 was detected in swans in Croatia and wild birds in Romania. More reports of bird infections are expected in the coming weeks, as are more reports in humans. There are unconfirmed reports of human cases in China.


The bilateral agreements, so far concentrated in Asia, will be expanded with the virus’s spread. The northern and southern American migratory flyways have less intersection than those in Asia, except for Alaska, where surveillance has been increased. There is a high probability that the H5N1 virus will be introduced into Africa and India.


The case fatality rate (CFR) fluctuates but remains high; the CFR currently is 51 percent overall, regardless of age. The clinical symptoms are similar to those of earlier cases, although diarrhea has become prominent in some. The second wave of infections occurred from August 2004 to the present; this is probably the third wave now. Only one (Thai) family cluster has confirmed human-to-human transmission, but such is possible in other cases.


A dendrogram illustrated the phylogenetic tree of the human glutenin genes of the viruses examined to date. Those causing the human infections in 2004 were in Clade 1, some of which were used to make candidate vaccine reference strains. Pilot lots of some are in trials. Clade 2 viruses are those seen this year in Turkey and Mongolia, and in the Indonesian human isolates. They also have been used previously to make reference vaccine viruses. No viruses from either clade yet spreads easily from person to person.


Conclusion. Avian influenza viruses pose a major risk to global public health. Early detection of human-to-human transmission is essential, and is very difficult in some rural areas of Asia. The heterogeneity of the Asian H5N1 viruses from 2003 through 2005 make the ongoing international collaboration even more important. Ongoing vaccine development, antiviral stockpiling, and pandemic preparedness is building. Animal surveillance and human-veterinary communication is essential.


Discussion:

  • To anticipate human-to-human transmission, researchers are looking for a genetic reassortment to a virus better adapted for human-to-human transmission, changes in the virus receptor binding areas that would facilitate transmission, and in other areas.

  • Dr. Lazlo Portman, of I.D. Biomedical, reported their work on Clade 1 viruses and hoped to get some Clade 2 isolates to continue their work. Dr. Cox will follow up on this matter.

  • Dr. Coelingh asked how different the antigenicity of the two clades would be, if cross-tested. Dr. Cox reported 8-fold or better, although this varies from virus to virus.

  • Dr. Turner asked if modeling is being done to estimate the relative risk of a pandemic at a particular point in time, perhaps based on past pandemic experience. Dr. Cox answered that the 1918 and 1950 H2 pandemic viruses were not highly pathogenic in birds (one advantage of that is the ability to track the virus’s development), and there are no data on how widespread H2 viruses were before those pandemics, nor H3 before the 1968 pandemic.

  • The reason that flock culling has not eliminated virus transmission is due in part to the common possession of backyard flocks and pet birds in Asia, and different methods of animal husbandry.

  • No large scale seroprevalence studies in Asia have been done; these are being encouraged by C.D.C.


Update on H5N1 Vaccine Clinical Trial

Presenter: Dr. John Treanor, University of Rochester


The inactivated vaccine candidates undergoing clinical trials now include:

  • The Clade 1, A/Vietnam/1203/04 strain is being manipulated with reverse genetics at St. Jude to replace the primary pathogenic factor, so that the seed virus can be handled under normal conditions for manufacture.

  • Egg-grown subunit vaccines have been produced by licensed manufacturers (sanofi pasteur and Chiron); these vaccines are developed in a very similar material to that used for conventional annual influenza vaccine production. Licensure would be sought for a strain change.

  • The University of Rochester is working on a subunit vaccine with no adjuvant, like the current influenza vaccine, to determine dose related safety and immunogenicity. But, rather than seeking a set point for the latter, they are looking for a seroneutralizing antibody level that, in the 1997 Hong Kong samples, seemed to differentiate infected from uninfected individuals.

The initial study of this was the N.I.H. DMID 4-063 trial at several of their V.T.E.U.s (Baylor College of Medicine, Cincinnati Children's Hospital, St. Louis University, UCLA, University at Maryland, University of Rochester, and Vanderbilt University). They evaluated the vaccine for safety and immunogenicity among healthy adults aged 18 to 64 years in a prospective, randomized, double-blind trial with a placebo group. Two I.M. vaccine doses (7.5, 15, 45 and 90 mcg, not all of hemagglutinin antigen) were given 28 days apart. Endpoints were safety, as measured by solicited and unsolicited adverse event reports, and immunogenicity, as measured by a neutralizing titer (that is, the reverse genetically engineered vaccine seed virus) of 1 per 40. The results of the immunogenicity assessment were used to proceed with planned studies in the elderly and among children, just now beginning.


Preliminary results of DMID 04-063 show that the vaccine was well tolerated at all doses. There was a dose-related increase of local pain/tenderness. Some neutralizing responses were seen at all doses, and the best responses were seen at high doses. The hemagglutination inhibition test, which was previously ineffective, became very sensitive to detecting response to the H5 virus. When chicken erythrocytes were replaced by horse erythrocytes, the hemagglutination inhibition test became sensitive to detect responses to the H5 virus, and correlated well with neutralizing response. Results and the trial database are expected to be finalized this November. That will provide a better idea of dose-related immunogenicity.


The status of several H5 vaccine trials was outlined:

04-063: Vaccine use in healthy adults: completed. A revaccination study of this cohort to assess immune memory is also planned.

05-0015: Vaccine administered I.D. versus I.M. for dose saving: complete.

04-076: Evaluation of 45 mcg and 90 mcg doses in the healthy elderly.

04-077: Vaccine for healthy children: beginning.

05-043: Revaccination of 1997 H5 Hong Kong vaccine recipients (Hong Kong 15697 virus, an antigenic variant different from the current 5 virus).


Future studies of dose-saving strategies include:

  • Evaluation of adjuvants (alum, MF59, MPL, and others).

  • Evaluation of administration route.

  • Evaluation of potential interaction with T.I.V., toward a quadrivalent with a pandemic component.

  • Live attenuated (cold adapted) H5 or H9 vaccines like FluMist, as vaccines or to verify protection (mock challenge). A collaboration of MedImmune, Janta Subbarao and others, this will be tested at Johns Hopkins.

  • Development of unconventional approaches such as DNA vaccines boosted by inactivated vaccines (farther in the future).


CLOSING COMMENTS

Dr. Abramson reported for Dr. Gellin that the next version of the influenza pandemic preparedness plan was due to be released in the next few weeks. Then, with no further comment, the meeting adjourned at 2:58 p.m.


I hereby certify that these minutes are accurate to the best of my knowledge.


Jon S. Abramson, MD, Chair


Date


Attachment #1: Attendance

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