JAMA
Vol. 302 No. 4, pp. 349-452, July 22/29, 2009
http://jama.ama-assn.org/current.dtl

Grand Rounds
Ancillary Care Obligations of Medical Researchers

Neal Dickert, MD, PhD; David Wendler, PhD
JAMA. 2009;302(4):424-428.

An investigator planning a study in Africa of the prevalence of pulmonary hypertension in children with severe malaria anticipates that she and her team will encounter significant unmet health needs during the course of the study. She recognizes that study procedures, particularly echocardiography, may identify and diagnose conditions that are not treatable within the local health system due to resource constraints. Aware that some of these needs may be serious, as well as difficult and costly to treat, she asks the bioethics consultation service for assistance in determining the extent to which she as an investigator has a responsibility to provide clinical care for conditions that she finds while conducting the study. This article reviews the issue of investigators’ responsibilities to meet participants’ needs for ancillary care and argues that investigators can have a responsibility to provide care for a wide range of health needs, including at times care for conditions not connected to the research question or study procedures. That responsibility, however, is significantly limited by the depth of the investigator’s relationship with participants and the resource demands of providing such care.

Commentaries
Ancillary Care for Public Health Research in Developing Countries
Adnan A. Hyder; Maria W. Merritt
JAMA. 2009;302(4):429-431.

[First 150 words per JAMA convention]
Belsky and Richardson1 defined ancillary care as care needed by research participants but not necessary to ensure scientific validity, prevent study-related harms, or address study-related injuries and introduced a framework for evaluating ancillary care based on 2 questions.2 Does a participant’s need for care fall within the scope of the investigator’s responsibility for the participant’s health, as defined by aspects of health implicitly entrusted to the investigator through the participant’s consent to comply with research procedures? If so, what is the strength of the participant’s moral claim on the investigator to address that need? The strength of the claim is modulated by attributes of the participant-investigator relationship, such as depth of involvement, degree of participant’s vulnerability, and degree of participant’s dependence, together with limits on available resources.2 Dickert et al3 questioned the narrow limits of Belsky and Richardson’s definition of . . .

The Lancet
Jul 25, 2009  Volume 374  Number 9686  Pages 265 – 356
http://www.thelancet.com/journals/lancet/issue/current

Comment
HPV vaccine for all
Karin B Michels, Harald zur Hausen

Preview
Cervical cancer is the second leading cause of death from cancer in women worldwide. Since the introduction of Papanicolaou smear-based screening in the 1950s, mortality from cervical cancer has declined over 70% in developed countries. The Pap test is a classic example of a highly effective public health intervention without knowledge about the actual cause of the disease. The main types of high-risk human papillomaviruses (HPV) were identified as causal agents only 30 years later, by the group of one of us (HzH).

Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women
J Paavonen, P Naud, J Salmerón, CM Wheeler, S-N Chow, D Apter, H Kitchener, X Castellsague, JC Teixeira, SR Skinner, J Hedrick, U Jaisamrarn, G Limson, S Garland, A Szarewski, B Romanowski, FY Aoki, TF Schwarz, WAJ Poppe, FX Bosch, D Jenkins, K Hardt, T Zahaf, D Descamps, F Struyf, M Lehtinen, G Dubin, for the HPV PATRICIA Study Group

Summary
Background
The human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine was immunogenic, generally well tolerated, and effective against HPV-16 or HPV-18 infections, and associated precancerous lesions in an event-triggered interim analysis of the phase III randomised, double-blind, controlled PApilloma TRIal against Cancer In young Adults (PATRICIA). We now assess the vaccine efficacy in the final event-driven analysis.

Methods
Women (15—25 years) were vaccinated at months 0, 1, and 6. Analyses were done in the according-to-protocol cohort for efficacy (ATP-E; vaccine, n=8093; control, n=8069), total vaccinated cohort (TVC, included all women receiving at least one vaccine dose, regardless of their baseline HPV status; represents the general population, including those who are sexually active; vaccine, n=9319; control, n=9325), and TVC-naive (no evidence of oncogenic HPV infection at baseline; represents women before sexual debut; vaccine, n=5822; control, n=5819). The primary endpoint was to assess vaccine efficacy against cervical intraepithelial neoplasia 2+ (CIN2+) that was associated with HPV-16 or HPV-18 in women who were seronegative at baseline, and DNA negative at baseline and month 6 for the corresponding type (ATP-E). This trial is registered with ClinicalTrials.gov, number NCT00122681.

Findings
Mean follow-up was 34·9 months (SD 6·4) after the third dose. Vaccine efficacy against CIN2+ associated with HPV-16/18 was 92·9% (96·1% CI 79·9—98·3) in the primary analysis and 98·1% (88·4—100) in an analysis in which probable causality to HPV type was assigned in lesions infected with multiple oncogenic types (ATP-E cohort). Vaccine efficacy against CIN2+ irrespective of HPV DNA in lesions was 30·4% (16·4—42·1) in the TVC and 70·2% (54·7—80·9) in the TVC-naive. Corresponding values against CIN3+ were 33·4% (9·1—51·5) in the TVC and 87·0% (54·9—97·7) in the TVC-naive. Vaccine efficacy against CIN2+ associated with 12 non-vaccine oncogenic types was 54·0% (34·0—68·4; ATP-E). Individual cross-protection against CIN2+ associated with HPV-31, HPV-33, and HPV-45 was seen in the TVC.

Interpretation
The HPV-16/18 AS04-adjuvanted vaccine showed high efficacy against CIN2+ associated with HPV-16/18 and non-vaccine oncogenic HPV types and substantial overall effect in cohorts that are relevant to universal mass vaccination and catch-up programmes.

Funding: GlaxoSmithKline Biologicals.

The Lancet Infectious Disease
Aug 2009  Volume 9  Number 8   Pages 455 – 520
http://www.thelancet.com/journals/laninf/issue/current

[Editor’s Note: This special themed issue of The Lancet Infectious Disease includes a number of commentaries and articles focused on influenza. We present the editorial overview here]

Leading Edge
Running faster to stay in the same place

The Lancet Infectious Diseases
For a UK based infectious diseases journal, albeit one with a global perspective, August would not, in any other year, be the obvious month for an influenza themed issue. But 2009 is not just any other year for influenza—for the first time in their careers, clinicians and researchers are facing the global challenge of an influenza pandemic. This issue also coincides with The Lancet Conference on Influenza in the Asia–Pacific to be held in Beijing, Aug 21–23, in which international experts come together to discuss various aspects of influenza research from insights on the virus, to surveillance, and, pertinently, pandemic response.

New England Journal of Medicine
Volume 361 — July 23, 2009 — Number 4
http://content.nejm.org/current.shtml

Editorial
Typhoid Vaccines Ready for Implementation
M. M. Levine

[Full text]
Enteric fevers encompass typhoid fever caused by Salmonella enterica serotype Typhi (S. Typhi) and paratyphoid fever caused by serotype Paratyphi A or B (S. Paratyphi). These human-restricted pathogens are acquired by ingesting contaminated water or food, and in the individual patient, one cannot differentiate clinically which agent is causing illness. S. Typhi expresses a capsular “Vi” (for virulence) polysaccharide, whereas S. Paratyphi A and B cannot synthesize Vi.

Before the use of antibiotics, typhoid fever had a case fatality rate of 10 to 20%. Transmission of enteric fever is minimized or eliminated if populations have access to treated water supplies and sanitation to remove human fecal matter. Where such amenities are unavailable, the risk of typhoid fever can be substantially diminished by immunization with typhoid vaccines.

Early typhoid vaccines (heat-inactivated whole S. Typhi organisms preserved in phenol) were developed in the 1890s. Six decades later, the World Health Organization (WHO) sponsored large-scale, randomized, controlled field trials, in which investigators found that similar killed whole-cell vaccines conferred substantial protection against typhoid.1 However, because these vaccines commonly elicited debilitating adverse reactions (fever and malaise), they were rarely used to control endemic typhoid fever.1

After a report in 1948 that chloramphenicol drastically ameliorated enteric fevers and reduced the case fatality rate to less than 1%, the treatment of patients with oral chloramphenicol became the mainstay of typhoid control in developing countries for the next quarter century. A rude awakening came in the 1970s, when epidemics of chloramphenicol-resistant typhoid occurred in Mexico and Vietnam. These outbreaks stimulated a search for alternative oral antibiotic therapies and accelerated efforts to develop a new generation of better-tolerated, efficacious typhoid vaccines. The efforts bore fruit when live oral S. Typhi vaccine strain Ty21a and parenteral Vi polysaccharide vaccine were licensed in the late 1980s and early 1990s. Despite extensive data documenting the safety, efficacy, and practicality of the Vi and Ty21a vaccines, they have not been widely applied programmatically in developing countries.

In the late 1980s, strains of S. Typhi that were resistant to multiple clinically relevant antibiotics began to emerge. In response, in 1999, the WHO recommended that typhoid vaccines be used for immunization of school-age children in areas where antibiotic-resistant typhoid was endemic. In 2008, the WHO and the Global Alliance for Vaccines and Immunization took more active steps to encourage programmatic use of these vaccines where typhoid is a health problem.

In most of the world, the incidence of enteric fever peaks among school-age children. However, in some South Asian urban slums, S. Typhi bacteremic infections peak in preschoolers, particularly when cases are detected by active household surveillance2,3; such infections are uncommon in infants. Since the WHO’s Expanded Program on Immunization does not typically include routine visits for toddlers or preschool children, protecting these age groups requires innovative strategies. One approach would be to administer typhoid vaccines in infancy, if efficacy could persist through the preschool and school years. Alternatively, preschool children could be targeted for mass campaigns. The current licensed typhoid vaccines are not compatible with infant immunization, since the unconjugated Vi vaccine is poorly immunogenic in infants, and the use of Ty21a in enteric-coated capsules is impractical.

In this issue of the Journal, Sur et al.4 report results of a well-executed field study showing that the Vi vaccine conferred an adjusted vaccine effectiveness of 80% in preschool children, thereby providing a biologic basis for including preschoolers in mass typhoid-immunization campaigns. However, organizing mass immunizations of so-called noncaptive populations such as preschoolers is more demanding than conducting campaigns among schoolchildren.

Sur et al. showed a trend for a lower adjusted Vi-vaccine effectiveness in older subjects (56% in children between the ages of 5 and 14 years and 46% in persons 15 years of age or older), although the differences in efficacy were not significant. These findings are the opposite of the trend observed in field trials of killed whole-cell parenteral vaccines and of the oral Ty21a vaccine, in which vaccine effectiveness was higher in older children.

A fascinating secondary analysis performed by Sur et al. indicated that control subjects who did not receive the Vi vaccine but lived in clusters with vaccinated subjects had substantial protection against typhoid fever. This is important new information. The indirect protection of nonvaccinated persons by the Vi vaccine further bolsters the case for school-based immunization to control endemic typhoid, since one might expect some indirect protection of preschool children as well. Indirect protection has also been observed with the oral Ty21a vaccine.1 Both Vi5 and Ty21a6 vaccines have been logistically practical and effective when administered to scores of thousands of schoolchildren through large-scale, school-based immunization projects.

An advantage of parenteral Vi vaccine is its single-dose regimen; unconjugated Vi does not elicit immunologic memory, so serum Vi titers are not boosted by additional doses. However, mass administration of the Vi vaccine by needle and syringe creates challenges for ensuring injection safety and for disposing of material that is potentially contaminated with bloodborne viruses. The use of needle-free injection devices could avert this problem. A drawback of the Ty21a vaccine is that it requires a three-dose regimen with an every-other-day interval. Nevertheless, oral immunization is logistically very practical in schoolchildren.

The Vi vaccine does not protect against S. Paratyphi A or B, since these strains do not express the Vi polysaccharide. Thus, countries with high rates of paratyphoid fever cannot expect reductions from the use of the Vi vaccine. The Ty21a vaccine confers substantial cross-protection (vaccine effectiveness, 49%) against S. Paratyphi B7 but not against S. Paratyphi A.8

In computer models, disease incidence and duration of protection greatly affect cost-effectiveness of typhoid vaccination in endemic settings. Field trials of the Vi vaccine have incorporated relatively short follow-up (17 months to 3 years),9,10 as compared with trials of the Ty21a vaccine (5 to 7 years).11 Klugman et al.10 reported a vaccine effectiveness of 55% during 3 years of follow-up. Investigation of a typhoid outbreak among Vi-immunized French soldiers in Africa showed that those who had received the vaccine more than 3 years before exposure had twice the risk of disease, as compared with those who had received the vaccine within the previous 3 years.12 Three doses of the Ty21a vaccine in enteric-coated capsules conferred a vaccine effectiveness of 62% during 7 years of follow-up.11

Two different “flavors” of licensed typhoid vaccine, parenteral unconjugated Vi and oral Ty21a, are available for use by public health practitioners. The time has come to implement use of these vaccines vigorously and monitor the effect of such intervention.

Dr. Levine reports receiving consulting fees from Merck and Medicago and research support from Medimmune and Merck and holding patents on potential components of live oral typhoid vaccines. No other potential conflict of interest relevant to this article was reported.

Source Information

From the Center for Vaccine Development, University of Maryland School of Medicine, Baltimore.

References

Levine MM, Ferreccio C, Black RE, Tacket CO, Germanier R. Progress in vaccines against typhoid fever. Rev Infect Dis 1989;11:Suppl 3:S552-S567. [Web of Science][Medline]

Sinha A, Sazawal S, Kumar R, et al. Typhoid fever in children aged less than 5 years. Lancet 1999;354:734-737. [CrossRef][Web of Science][Medline]

Brooks WA, Hossain A, Goswami D, et al. Bacteremic typhoid fever in children in an urban slum, Bangladesh. Emerg Infect Dis 2005;11:326-329. [Web of Science][Medline]

Sur D, Ochiai RL, Bhattacharya SK, et al. A cluster-randomized effectiveness trial of Vi typhoid vaccine in India. N Engl J Med 2009;361:335-344. [Free Full Text]

Ochiai RL, Acosta CJ, Agtini M, et al. The use of typhoid vaccines in Asia: the DOMI experience. Clin Infect Dis 2007;45:Suppl 1:S34-S38. [CrossRef][Web of Science][Medline]

Ferreccio C, Levine MM, Rodriguez H, Contreras R. Comparative efficacy of two, three, or four doses of Ty21a live oral typhoid vaccine in enteric-coated capsules: a field trial in an endemic area. J Infect Dis 1989;159:766-769. [Web of Science][Medline]

Levine MM, Ferreccio C, Black RE, Lagos R, Martin OS, Blackwelder WC. Ty21a live oral typhoid vaccine and prevention of paratyphoid fever caused by Salmonella enterica serovar Paratyphi B. Clin Infect Dis 2007;45:Suppl 1:S24-S28. [CrossRef][Web of Science][Medline]

Simanjuntak CH, Paleologo FP, Punjabi NH, et al. Oral immunisation against typhoid fever in Indonesia with Ty21a vaccine. Lancet 1991;338:1055-1059. [CrossRef][Web of Science][Medline]

Acharya IL, Lowe CU, Thapa R, et al. Prevention of typhoid fever in Nepal with the Vi capsular polysaccharide of Salmonella typhi: a preliminary report. N Engl J Med 1987;317:1101-1104. [Abstract]

Klugman KP, Koornhof HJ, Robbins JB, Le Cam NN. Immunogenicity, efficacy and serological correlate of protection of Salmonella typhi Vi capsular polysaccharide vaccine three years after immunization. Vaccine 1996;14:435-438. [CrossRef][Web of Science][Medline]

Levine MM, Ferreccio C, Abrego P, Martin OS, Ortiz E, Cryz S. Duration of efficacy of ty21a, attenuated Salmonella typhi live oral vaccine. Vaccine 1999;17:Suppl 2:S22-S27. [CrossRef][Web of Science][Medline]

Michel R, Garnotel E, Spiegel A, Morillon M, Saliou P, Boutin JP. Outbreak of typhoid fever in vaccinated members of the French Armed Forces in the Ivory Coast. Eur J Epidemiol 2005;20:635-642. [CrossRef][Web of Science][Medline]

New England Journal of Medicine
Volume 361 — July 23, 2009 — Number 4
http://content.nejm.org/current.shtml

Original Article
A Cluster-Randomized Effectiveness Trial of Vi Typhoid Vaccine in India
D. Sur and Others

ABSTRACT
Background Typhoid fever remains an important cause of illness and death in the developing world. Uncertainties about the protective effect of Vi polysaccharide vaccine in children under the age of 5 years and about the vaccine’s effect under programmatic conditions have inhibited its use in developing countries.

Methods We conducted a phase 4 effectiveness trial in which slum-dwelling residents of Kolkata, India, who were 2 years of age or older were randomly assigned to receive a single dose of either Vi vaccine or inactivated hepatitis A vaccine, according to geographic clusters, with 40 clusters in each study group. The subjects were then followed for 2 years.

Results A total of 37,673 subjects received a dose of a study vaccine. The mean rate of vaccine coverage was 61% for the Vi vaccine clusters and 60% for the hepatitis A vaccine clusters. Typhoid fever was diagnosed in 96 subjects in the hepatitis A vaccine group, as compared with 34 in the Vi vaccine group, with no subject having more than one episode. The level of protective effectiveness for the Vi vaccine was 61% (95% confidence interval [CI], 41 to 75; P<0.001 for the comparison with the hepatitis A vaccine group). Children who were vaccinated between the ages of 2 and 5 years had a level of protection of 80% (95% CI, 53 to 91). Among unvaccinated members of the Vi vaccine clusters, the level of protection was 44% (95% CI, 2 to 69). The overall level of protection among all residents of Vi vaccine clusters was 57% (95% CI, 37 to 71). No serious adverse events that were attributed to either vaccine were observed during the month after vaccination.

Conclusions The Vi vaccine was effective in young children and protected unvaccinated neighbors of Vi vaccinees. The potential for combined direct and indirect protection by Vi vaccine should be considered in future deliberations about introducing this vaccine in areas where typhoid fever is endemic. (ClinicalTrials.gov number, NCT00125008 [ClinicalTrials.gov] .)

Pediatrics
August 2009 / VOLUME 124 / ISSUE 2
http://pediatrics.aappublications.org/current.shtml

Article
A Stepped Intervention Increases Well-Child Care and Immunization Rates in a Disadvantaged Population

Simon J. Hambidge, MD, PhDa,b,c,d, Stephanie L. Phibbs, MPHd, Vijayalaxmi Chandramouli, MSd, Diane Fairclough, DrPHd and John F. Steiner, MD, MPHd,e
a Denver Community Health Services, Denver Health, Denver, Colorado; Departments of
b Pediatrics
c Preventive Medicine and Biometrics
e General Internal Medicine
d Colorado Health Outcomes Program, University of Colorado School of Medicine, Denver, Colorado

OBJECTIVE: To test a stepped intervention of reminder/recall/case management to increase infant well-child visits and immunization rates.

METHODS: We conducted a randomized, controlled, practical, clinical trial with 811 infants born in an urban safety-net hospital and followed through 15 months of life. Step 1 (all infants) involved language-appropriate reminder postcards for every well-child visit. Step 2 (infants who missed an appointment or immunization) involved telephone reminders plus postcard and telephone recall. Step 3 (infants still behind on preventive care after steps 1 and 2) involved intensive case management and home visitation.

RESULTS: Infants in the intervention arm, compared with control infants, had significantly fewer days without immunization coverage in the first 15 months of life (109 vs 192 days P < .01) and were more likely to have 5 well-child visits (65% vs 47% P < .01). In multivariate analyses, infants in the intervention arm were more likely than control infants to be up to date with 12-month immunizations and to have had 5 well-child visits. The cost per child was $23.30 per month.

CONCLUSION: This stepped intervention of tracking and case management improved infant immunization status and receipt of preventive care in a population of high-risk urban infants of low socioeconomic status.

Vaccine
Volume 27, Issue 37, Pages 5027-5170 (13 August 2009)
http://www.sciencedirect.com/science/journal/0264410X

Conference Report
The fight against rabies in Africa: From recognition to action
Pages 5027-5032
Betty Dodet and the Africa Rabies Bureau (AfroREB)

Abstract
As a follow-up to the first AfroREB meeting, held in Grand Bassam (Côte d’Ivoire) in March 2008, African rabies experts of the AfroREB network met a second time to complete the evaluation of the rabies situation in Africa and define specific action plans. About 40 French speaking rabies specialists from northern, western and central Africa and Madagascar met in Dakar (Senegal), from 16 to 19 March 2009. With the participation of delegates from Tunisia, who joined the AfroREB network this year, 15 French speaking African countries were represented. Experts from the Institut Pasteur in Paris, the Alliance for Rabies Control, and the Southern and Eastern African Rabies Group (SEARG, a network of rabies experts from 19 English speaking Southern and Eastern African countries) were in attendance, to participate in the discussion and share their experiences.

It was unanimously agreed that the priority is to break the vicious cycle of indifference and lack of information which is the main barrier to human rabies prevention.

Vaccine
Volume 27, Issue 37, Pages 5027-5170 (13 August 2009)
http://www.sciencedirect.com/science/journal/0264410X

Review
Influenza control in the 21st century: Optimizing protection of older adults
Pages 5043-5053
Arnold S. Monto, Filippo Ansaldi, Richard Aspinall, Janet E. McElhaney, Luis F. Montaño, Kristin L. Nichol, Joan Puig-Barberà, Joe Schmitt, Iain Stephenson

Abstract
Older adults (≥65 years of age) are particularly vulnerable to influenza illness. This is due to a waning immune system that reduces their ability to respond to infection, which leads to more severe cases of disease. The majority (90%) of influenza-related deaths occur in older adults and, in addition, catastrophic disability resulting from influenza-related hospitalization represents a significant burden in this vulnerable population. Current influenza vaccines provide benefits for older adults against influenza; however, vaccine effectiveness is lower than in younger adults. In addition, antigenic drift is also a concern, as it can impact on vaccine effectiveness due to a mismatch between the vaccine virus strain and the circulating virus strain. As such, vaccines that offer higher and broader protection against both homologous and heterologous virus strains are desirable. Approaches currently available in some countries to meet this medical need in older adults may include the use of adjuvanted vaccines. Future strategies under evaluation include the use of high-dose vaccines; novel or enhanced adjuvantation of current vaccines; use of live attenuated vaccines in combination with current vaccines; DNA vaccines; recombinant vaccines; as well as the use of different modes of delivery and alternative antigens. However, to truly evaluate the benefits that these solutions offer, further efficacy and effectiveness studies, and better correlates of protection, including a precise measurement of the T cell responses that are markers for protection, are needed. While it is clear that vaccines with greater immunogenicity are required for older adults, and that adjuvanted vaccines may offer a short-term solution, further research is required to exploit the many other new technologies.

Vaccine
Volume 27, Issue 37, Pages 5027-5170 (13 August 2009)
http://www.sciencedirect.com/science/journal/0264410X

Regular Papers
The Australian Childhood Immunisation Register—A model for universal immunisation registers?
Pages 5054-5060
Brynley P. Hull, Shelley L. Deeks, Peter B. McIntyre

Abstract
The Australian Childhood Immunisation Register (ACIR) was established in 1996 as an opt-out register built on the platform of Medicare, the universal national health insurance scheme. Introduction of financial incentives for providers and parents, linked to the ACIR, followed from 1998. Over the subsequent decade, national levels for receipt of all vaccines by 12, 24 and 72 months of age have risen to 91%, 93%, and 88%, respectively. Conscientious objection to immunisation can be registered, with retention of eligibility for incentives. The ACIR has been important in implementation of a range of measures to improve childhood immunisation coverage in Australia. Linkage of a universal childhood immunisation register to national health insurance schemes has potential applicability in a variety of settings internationally.

Vaccine
Volume 27, Issue 37, Pages 5027-5170 (13 August 2009)
http://www.sciencedirect.com/science/journal/0264410X

Cost-effectiveness analysis of human papillomavirus-vaccination programs to prevent cervical cancer in Austria
Pages 5133-5141
Ingrid Zechmeister, Birgitte Freiesleben de Blasio, Geoff Garnett, Aileen Rae Neilson, Uwe Siebert

Abstract
Objective
The study predicts long-term cervical cancer related population health and economic effects of introducing the HPV-vaccination for 12-year-old girls (and boys) in addition to current screening compared with screening only.

Method
Health effects are predicted by a dynamic transmission model. Model results are used to calculate incremental cost-effectiveness ratios (ICER) in € per life year gained (LYG) for a time-horizon between 2008 and 2060 from a public payer and a societal perspective.

Results
Vaccination of girls results a discounted ICER of € 64,000/LYG and € 50,000/LYG from a payer’s and societal perspectives respectively. The additional vaccination of boys increases the ICER to € 311,000 and € 299,000/LYG respectively. Results were most sensitive to vaccination price, discount rate and time-horizon.

Conclusion
HPV-vaccination for girls should be cost-effective when adopting a longer time-horizon and a societal perspective. Applying a shorter time frame and a payer’s perspective or vaccinating boys may not be cost-effective without reducing the vaccine price.

The WHO shifted its monitoring and reporting strategy continues on A/(H1N1), concluding its series of regular updates with #58 issued 6 July 2009 (just below). The change was discussed in the third of a new series of “briefing notes” as provided in full text below.

– Pandemic (H1N1) 2009 – update 58

6 July 2009 – The title of this update has now evolved to “Pandemic (H1N1) 2009.” WHO notes 94,512 officially reported cases of influenza A(H1N1) infection (up from 59,814 a week ago and 44,287 a week earlier), including 429 deaths (up from 263 a week ago and 180 a week earlier). http://www.who.int/csr/don/2009_07_06/en/index.html

The WHO appears to be continuing what is now a monthly update in A/(H5N1) with the last report issued 1 July 2009:

– Cumulative Number of Confirmed Human Cases of Avian Influenza A/(H5N1) Reported to WHO

1 July 2009  The published tabular chart reports 436 confirmed cases (up from 433 cases reported as of 2 June 2009) and 262 deaths (unchanged from the 2 June 2009 report).

http://www.who.int/csr/disease/avian_influenza/country/cases_table_2009_06_02/en/index.html

Pandemic (H1N1) 2009 briefing note 2

WHO recommendations on pandemic (H1N1) 2009 vaccines

13 JULY 2009 | GENEVA — On 7 July 2009, the Strategic Advisory Group of Experts (SAGE) on Immunization held an extraordinary meeting in Geneva to discuss issues and make recommendations related to vaccine for the pandemic (H1N1) 2009.

SAGE reviewed the current pandemic situation, the current status of seasonal vaccine production and potential A(H1N1) vaccine production capacity, and considered potential options for vaccine use.

The experts identified three different objectives that countries could adopt as part of their pandemic vaccination strategy: protect the integrity of the health-care system and the country’s critical infrastructure; reduce morbidity and mortality; and reduce transmission of the pandemic virus within communities.

Countries could use a variety of vaccine deployment strategies to reach these objectives but any strategy should reflect the country’s epidemiological situation, resources and ability to access vaccine, to implement vaccination campaigns in the targeted groups, and to use other non-vaccine mitigation measures.

Although the severity of the pandemic is currently considered to be moderate with most patients experiencing uncomplicated, self-limited illness, some groups such as pregnant women and persons with asthma and other chronic conditions such as morbid obesity appear to be at increased risk for severe disease and death from infection.

Since the spread of the pandemic virus is considered unstoppable, vaccine will be needed in all countries. SAGE emphasized the importance of striving to achieve equity among countries to access vaccines developed in response to the pandemic (H1N1) 2009

The following recommendations were provided to the WHO Director-General:

–  All countries should immunize their health-care workers as a first priority to protect the essential health infrastructure. As vaccines available initially will not be sufficient, a step-wise approach to vaccinate particular groups may be considered. SAGE suggested the following groups for consideration, noting that countries need to determine their order of priority based on country-specific conditions: pregnant women; those aged above 6 months with one of several chronic medical conditions; healthy young adults of 15 to 49 years of age; healthy children; healthy adults of 50 to 64 years of age; and healthy adults of 65 years of age and above.

–  Since new technologies are involved in the production of some pandemic vaccines, which have not yet been extensively evaluated for their safety in certain population groups, it is very important to implement post-marketing surveillance of the highest possible quality. In addition, rapid sharing of the results of immunogenicity and post-marketing safety and effectiveness studies among the international community will be essential for allowing countries to make necessary adjustments to their vaccination policies.

–  In view of the anticipated limited vaccine availability at global level and the potential need to protect against “drifted” strains of virus, SAGE recommended that promoting production and use of vaccines such as those that are formulated with oil-in-water adjuvants and live attenuated influenza vaccines was important.

As most of the production of the seasonal vaccine for the 2009-2010 influenza season in the northern hemisphere is almost complete and is therefore unlikely to affect production of pandemic vaccine, SAGE did not consider that there was a need to recommend a “switch” from seasonal to pandemic vaccine production.

WHO Director-General Dr Margaret Chan endorsed the above recommendations on 11 July 2009, recognizing that they were well adapted to the current pandemic situation. She also noted that the recommendations will need to be changed if and when new evidence become available…

http://www.who.int/csr/disease/swineflu/notes/h1n1_vaccine_20090713/en/index.html

Pandemic (H1N1) 2009 briefing note 3 (revised)

Changes in reporting requirements for pandemic (H1N1) 2009 virus infection

16 JULY 2009 | GENEVA — As the 2009 pandemic evolves, the data needed for risk assessment, both within affected countries and at the global level, are also changing.

At this point, further spread of the pandemic, within affected countries and to new countries, is considered inevitable.

This assumption is fully backed by experience. The 2009 influenza pandemic has spread internationally with unprecedented speed. In past pandemics, influenza viruses have needed more than six months to spread as widely as the new H1N1 virus has spread in less than six weeks.

The increasing number of cases in many countries with sustained community transmission is making it extremely difficult, if not impossible, for countries to try and confirm them through laboratory testing. Moreover, the counting of individual cases is now no longer essential in such countries for monitoring either the level or nature of the risk posed by the pandemic virus or to guide implementation of the most appropriate response measures.

Monitoring still needed

This pandemic has been characterized, to date, by the mildness of symptoms in the overwhelming majority of patients, who usually recover, even without medical treatment, within a week of the onset of symptoms. However, there is still an ongoing need in all countries to closely monitor unusual events, such as clusters of cases of severe or fatal pandemic (H1N1) 2009 virus infection, clusters of respiratory illness requiring hospitalization, or unexplained or unusual clinical patterns associated with serious or fatal cases.

Other potential signals of change in the currently prevailing pattern include unexpected, unusual or notable changes in patterns of transmission. Signals to be vigilant for include spikes in rates of absenteeism from schools or workplaces, or a more severe disease pattern, as suggested by, for example, a surge in emergency department visits.

In general, indications that health services are having difficulty coping with cases mean that such systems are under stress but they may also be a signal of increasing cases or a more severe clinical picture.

A strategy that concentrates on the detection, laboratory confirmation and investigation of all cases, including those with mild illness, is extremely resource-intensive. In some countries, this strategy is absorbing most national laboratory and response capacity, leaving little capacity for the monitoring and investigation of severe cases and other exceptional events.

Regular updates on newly affected countries

For all of these reasons, WHO will no longer issue the global tables showing the numbers of confirmed cases for all countries. However, as part of continued efforts to document the global spread of the H1N1 pandemic, regular updates will be provided describing the situation in the newly affected countries. WHO will continue to request that these countries report the first confirmed cases and, as far as feasible, provide weekly aggregated case numbers and descriptive epidemiology of the early cases.

For countries already experiencing community-wide transmission, the focus of surveillance activities will shift to reporting against the established indicators for the monitoring of seasonal influenza activity. Those countries are no longer required to submit regular reports of individual laboratory-confirmed cases to WHO.

Monitoring the virological characteristics of the pandemic virus will be important throughout the pandemic and some countries have well-established laboratory-based surveillance systems in place already for seasonal influenza virus monitoring. Even in countries with limited laboratory capacity, WHO recommends that the initial virological assessment is followed by the testing of at least 10 samples per week in order to confirm that disease activity is due to the pandemic virus and to monitor changes in the virus that may be important for case management and vaccine development.

Updated WHO guidelines for global surveillance reflect in greater detail these recommended changes, in line with reporting requirements set out in the International Health Regulations.

http://www.who.int/csr/disease/swineflu/notes/h1n1_surveillance_20090710/en/index.html

HHS Secretary Kathleen Sebelius announced that the department “will commit US$884 million to purchase additional supplies of two key ingredients for potential H1N1 vaccine to further prepare the nation for a potential resurgence of the 2009 H1N1 virus.” Secretary Sebelius said, “We recognize that preparedness is shared responsibility between federal, tribal, state, local governments, private organizations and individuals. We are doing our part to be as prepared as possible for the impact that this infectious disease could have on our country. Vaccines may serve an important role in that preparedness. The action we are taking today will provide flexibility in a future immunization program, if a program is recommended.”

The funds will be used to place additional orders for bulk H1N1 antigen and adjuvant on existing contracts with Sanofi Pasteur, MedImmune, GlaxoSmithKline and Novartis. The vaccine ingredients will become a part of the pandemic stockpile, for use if a vaccination campaign is necessary, HHS said. More information about this announcement: https://www.medicalcountermeasures.gov/BARDA/MCM/panflu/factsheet.aspx.

(HHS Release, 13 July 2009) http://www.hhs.gov/news.

The MMWR Weekly: July 17, 2009 / 58(27);749-752 includes:
Intensive-Care Patients With Severe Novel Influenza A (H1N1) Virus Infection — Michigan, June 2009

On July 10, 2009, this report was posted as an MMWR Dispatch on the MMWR website (http://www.cdc.gov/mmwr).
“In April 2009, CDC reported the first two cases in the United States of human infection with a novel influenza A (H1N1) virus (1). As of July 6, a total of 122 countries had reported 94,512 cases of novel influenza A (H1N1) virus infection, 429 of which were fatal; in the United States, a total of 33,902 cases were reported, 170 of which were fatal.* Cases of novel influenza A (H1N1) virus infection have included rapidly progressive lower respiratory tract disease resulting in respiratory failure, development of acute respiratory distress syndrome (ARDS), and prolonged intensive care unit (ICU) admission (2). Since April 26, communitywide transmission of novel influenza A (H1N1) virus has occurred in Michigan, with 655 probable and confirmed cases reported as of June 18 (Michigan Department of Community Health [MDCH], unpublished data, 2009).

“This report summarizes the clinical characteristics of a series of 10 patients with novel influenza A (H1N1) virus infection and ARDS at a tertiary-care ICU in Michigan. Of the 10 patients, nine were obese (body mass index [BMI] ≥30), including seven who were extremely obese (BMI ≥40); five had pulmonary emboli; and nine had multiorgan dysfunction syndrome (MODS). Three patients died. Clinicians should be aware of the potential for severe complications of novel influenza A (H1N1) virus infection, particularly in extremely obese patients…”

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5827a4.htm

The Weekly Epidemiological Record (WER) for 17 July 2009, vol. 84, 29 (pp 289–300) includes: Advisory Committee on Poliomyelitis Eradication: recommendations on the use of bivalent oral poliovirus vaccine types 1 and 3; Status of neonatal tetanus elimination in the United Republic of Tanzania – results from a lot quality-assurance cluster survey; Pandemic (H1N1) 2009 briefing note 1 – Viruses resistant to oseltamivir (Tamiflu) identified.

http://www.who.int/wer/2009/wer8429.pdf

JAMA
Vol. 302 No. 3, pp. 227-340, July 15, 2009
http://jama.ama-assn.org/current.dtl

Medical News & Perspectives
Unvaccinated Children Face Pertussis Risk: Some Parents Fear Vaccine More Than Infection
Mike Mitka
JAMA. 2009;302(3):242-244.

[First 100 words per JAMA convention]
A new study shows that children who are not vaccinated for pertussis because of parental refusal have a higher risk of contracting the disease, but whether this news will help convince parents ambivalent about immunization remains to be seen.

The case-control study (Glanz JM et al. Pediatrics. 2009;123[6]:1446-1451) of 156 laboratory-confirmed pertussis cases between 1996 and 2007 found that while unvaccinated children made up about 0.5% of the examined population, they accounted for about 12% of the pertussis cases. “Many of the parents who refuse have the common perception that their child is not at risk—that they are protected by proxy—and our study showed that they are at risk and highlights the need to immunize,” said Jason M. Glanz, PhD, lead author and an epidemiologist with Kaiser Permanente Colorado’s Institute for Health Research…”

Journal of Infectious Diseases
15 August 2009   Volume 200, Number 4
http://www.journals.uchicago.edu/toc/jid/current

Editorial Commentaries
Influenza in Hospitalized Adults: Gaining Insight into a Significant Problem
Michael G. Ison

Major Articles and Brief Reports
Viruses
Viral Loads and Duration of Viral Shedding in Adult Patients Hospitalized with Influenza

Nelson Lee, Paul K. S. Chan, David S. C. Hui, Timothy H. Rainer, Eric Wong, Kin-Wing Choi, Grace C. Y. Lui, Bonnie C. K. Wong, Rita Y. K. Wong, Wai-Yip Lam, Ida M. T. Chu, Raymond W. M. Lai, Clive S. Cockram, and Joseph J. Y. Sung

Background.The goal of this study was to characterize viral loads and factors affecting viral clearance in persons with severe influenza.

Methods.This was a 1-year prospective, observational study involving consecutive adults hospitalized with influenza. Nasal and throat swabs were collected at presentation, then daily until 1 week after symptom onset. Real‐time reverse‐transcriptase polymerase chain reaction to determine viral RNA concentration and virus isolation were performed. Viral RNA concentration was analyzed using multiple linear or logistic regressions or mixed-effect models.

Results.One hundred forty-seven inpatients with influenza A (H3N2) infection were studied (mean age ± standard deviation, years). Viral RNA concentration at presentation positively correlated with symptom scores and was significantly higher than that among time-matched outpatients (control subjects). Patients with major comorbidities had high viral RNA concentration even when presenting >2 days after symptom onset (mean ± standard deviation, vs log10 copies/mL; ; β, +0.86 [95% confidence interval, +0.03 to +1.68]). Viral RNA concentration demonstrated a nonlinear decrease with time; 26% of oseltamivir‐treated and 57% of untreated patients had RNA detected at 1 week after symptom onset. Oseltamivir started on or before symptom day 4 was independently associated with an accelerated decrease in viral RNA concentration (mean β [standard error], −1.19 [0.43] and −0.68 [0.33] log10 copies/mL for patients treated on day 1 and days 2–3, respectively; ) and viral RNA clearance at 1 week (odds ratio, 0.10 [95% confidence interval, 0.03–0.35] and 0.30 [0.10–0.90] for patients treated on day 1–2 and day 3–4, respectively). Conversely, major comorbidities and systemic corticosteroid use for asthma or chronic obstructive pulmonary disease exacerbations were associated with slower viral clearance. Viral RNA clearance was associated with a shorter hospital stay (7.0 vs 13.5 days; ).

Conclusion.Patients hospitalized with severe influenza have more active and prolonged viral replication. Weakened host defenses slow viral clearance, whereas antivirals started within the first 4 days of illness enhance viral clearance.

New England Journal of Medicine
Volume 361 — July 16, 2009 — Number 3
http://content.nejm.org/current.shtml

Review Article
Current Concepts: Historical Perspective — Emergence of Influenza A (H1N1) Viruses
S. M. Zimmer and D. S. Burke

[First 100 words and section headings per NEJM convention]
On April 17, 2009, officials at the Centers for Disease Control and Prevention (CDC) confirmed two cases of swine influenza in children living in neighboring counties in California.1 Here we take a perspective from systems biology to review the series of evolutionary and epidemiologic events, starting in 1918, that led to the emergence of the current swine-origin influenza A (H1N1) strain (S-OIV), which is widely known as swine flu. This article is one of two historical articles on influenza A (H1N1) viruses in this issue of the Journal. Our review focuses on the key steps that characterize this viral…

– Emergence of a Virus

– Simultaneous Appearance in Humans and Swine (1918)

– Antigenic Divergence of Human and Swine Influenza (1918–1930)

– Evolution of the 1918 Virus in Humans (1918–Present)

– Intrasubtypic Reassortment of Human H1N1 Virus (1947)

– Extinction of Human H1N1 Virus (1957)

– Sporadic Cross-Species Transfers (1958–Present)

– H1N1 Reemergence in Humans (1977)

– Seasonal Influenza A (H1N1) (1977–Present)

– Emergence of New H1N1 Strains in Swine (1979–Present)

– Sporadic Cross-Species Transmission of Triple Reassortant Virus (1998–2009)

– Reassortment of Two H1 Swine Viruses (2008–2009)

– Competition between Seasonal and Newly Emerged Viruses

Science
10 July 2009  Vol 325, Issue 5937, Pages 117-232
http://www.sciencemag.org/current.dtl

Perspectives
Epidemiology:
Does Viral Diversity Matter?

Graham F. Medley1 and D. James Nokes1,2

Epidemic viruses, such as severe acute respiratory syndrome (SARS) and influenza A, cause diseases that rapidly spread to many people, and seem to attract more scientific and public attention than do endemic viruses, which are continually present in populations. Yet endemic viruses cause far greater disability and death. But epidemic viruses are endemic somewhere, or will become so, and endemic viruses are often recurrently epidemic. So developing a full understanding of the mechanisms that promote and drive endemicity is key to reducing the overall burden of viral disease and reducing the risk of future, widespread pandemics. On page 290 of this issue, Pitzer et al. (1) investigate the causes of epidemics of rotavirus, a major, global endemic virus.

1 Department of Biological Sciences, University of Warwick, Coventry CV4 7AL, UK.
2 Kenya Medical Research Institute-Wellcome Trust Research Programme, Kilifi, Kenya.

Science
10 July 2009  Vol 325, Issue 5937, Pages 117-232

http://www.sciencemag.org/current.dtl

Research Articles
Demographic Variability, Vaccination, and the Spatiotemporal Dynamics of Rotavirus Epidemics

Virginia E. Pitzer,1,2,* Cécile Viboud,2 Lone Simonsen,3 Claudia Steiner,4 Catherine A. Panozzo,5 Wladimir J. Alonso,2 Mark A. Miller,2 Roger I. Glass,2 John W. Glasser,5 Umesh D. Parashar,5 Bryan T. Grenfell1,2,6

Historically, annual rotavirus activity in the United States has started in the southwest in late fall and ended in the northeast 3 months later; this trend has diminished in recent years. Traveling waves of infection or local environmental drivers cannot account for these patterns. A transmission model calibrated against epidemiological data shows that spatiotemporal variation in birth rate can explain the timing of rotavirus epidemics. The recent large-scale introduction of rotavirus vaccination provides a natural experiment to further test the impact of susceptible recruitment on disease dynamics. The model predicts a pattern of reduced and lagged epidemics postvaccination, closely matching the observed dynamics. Armed with this validated model, we explore the relative importance of direct and indirect protection, a key issue in determining the worldwide benefits of vaccination.

1 Center for Infectious Disease Dynamics, Pennsylvania State University, State College, PA 16801, USA.
2 Fogarty International Center, National Institutes of Health, Bethesda, MD 20892, USA.
3 School of Public Health and Health Services, George Washington University, Washington, DC 20052, USA.
4 Healthcare Cost and Utilization Project, Center for Delivery, Organization and Markets, Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services, Rockville, MD 20850, USA.
5 Epidemiology Branch, Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
6 Department of Ecology and Evolutionary Biology and Woodrow Wilson School, Princeton University, Princeton, NJ 08544, USA.

Vaccine
Volume 27, Issue 36, Pages 4875-5026 (6 August 2009)
http://www.sciencedirect.com/science/journal/0264410X

Cost-effectiveness of pneumococcal polysaccharide vaccination in adults: A systematic review of conclusions and assumptions
Pages 4891-4904
Isla Ogilvie, Antoine El Khoury, Yadong Cui, Erik Dasbach, John D. Grabenstein, Mireille Goetghebeur

Abstract
Streptococcus pneumoniae infections in adults are associated with substantial morbidity, mortality, and costs. A literature review was conducted to identify strengths and limitations of the cost-effectiveness of pneumococcal polysaccharide vaccine studies. A comparative analysis of the impact of model parameters on cost-effectiveness ratios was complemented by systematic assessment of the studies. We identified 11 economic evaluations of pneumococcal polysaccharide vaccine (PPV-23) in adults. In general, all 11 studies found that vaccination with PPV-23 is a cost-effective, and in some cases a cost-saving strategy for the prevention of invasive pneumococcal disease (IPD). The systematic assessment indicated that the results of the cost-effectiveness studies of PPV-23 are influenced by the values applied to vaccine efficacy, IPD incidence and case-fatality.

Vaccine
Volume 27, Issue 36, Pages 4875-5026 (6 August 2009)
http://www.sciencedirect.com/science/journal/0264410X

Cost of routine immunization of young children against rotavirus infection with Rotarix versus RotaTeq
Pages 4930-4937
Derek Weycker, Oleg Sofrygin, Jason E. Kemner, Stephen I. Pelton, GerryOster

Abstract
Using a probabilistic model of the clinical and economic burden of rotavirus gastroenteritis (RVGE), we estimated the expected impact of vaccinating a US birth cohort with Rotarix in lieu of RotaTeq. Assuming full vaccination of all children, use of Rotarix – rather than RotaTeq – was estimated to reduce the total number of RVGE events by 5% and associated costs by 8%. On an overall basis, Rotarix would reduce costs by $77.2 million (95% CI $71.5–$86.5). Similar reductions with Rotarix were estimated to occur under an assumption of incomplete immunization of children.

Vaccine
Volume 27, Issue 36, Pages 4875-5026 (6 August 2009)
http://www.sciencedirect.com/science/journal/0264410X

Evaluation of two live attenuated cold-adapted H5N1 influenza virus vaccines in healthy adults
Pages 4953-4960
Ruth A. Karron, Kawsar Talaat, Catherine Luke, Karen Callahan, Bhagvanji Thumar, Susan DiLorenzo, Josephine McAuliffe, Elizabeth Schappell, Amorsolo Suguitan, Kimberly Mills, Grace Chen, Elaine Lamirande, Kathleen Coelingh, Hong Jin, Brian R. Murphy, George Kemble, Kanta Subbarao

Abstract
Background
Development of live attenuated influenza vaccines (LAIV) against avian viruses with pandemic potential is an important public health strategy.

Methods and findings
We performed open-label trials to evaluate the safety, infectivity, and immunogenicity of H5N1 VN 2004 AA ca and H5N1 HK 2003 AA ca. Each of these vaccines contains a modified H5 hemagglutinin and unmodified N1 neuraminidase from the respective wild-type (wt) parent virus and the six internal protein gene segments of the A/Ann Arbor/6/60 cold-adapted (ca) master donor virus. The H5N1 VN 2004 AA ca vaccine virus was evaluated at dosages of 106.7 TCID50 and 107.5 TCID50, and the H5N1 HK 2003 AA ca vaccine was evaluated at a dosage of 107.5 TCID50. Two doses were administered intranasally to healthy adults in isolation at 4–8 week intervals. Vaccine safety was assessed through daily examinations and infectivity was assessed by viral culture and by realtime reverse transcription-polymerase chain reaction testing of nasal wash (NW) specimens. Immunogenicity was assessed by measuring hemagglutination-inhibition (HI) antibodies, neutralizing antibodies, and IgG or IgA antibodies to recombinant (r)H5 VN 2004 hemagglutinin (HA) in serum or NW.

Fifty-nine participants were enrolled: 21 received 106.7 TCID50 and 21 received 107.5 TCID50 of H5N1 VN 2004 AA ca and 17 received H5N1 HK 2003 AA ca. Shedding of vaccine virus was minimal, as were HI and neutralizing antibody responses. Fifty-two percent of recipients of 107.5 TCID50 of H5N1 VN 2004 AA ca developed a serum IgA response to rH5 VN 2004 HA.

Conclusions
The live attenuated H5N1 VN 2004 and HK 2003 AA ca vaccines bearing avian H5 HA antigens were very restricted in replication and were more attenuated than seasonal LAIV bearing human H1, H3 or B HA antigens. The H5N1 AA ca LAIV elicited serum ELISA antibody but not HI or neutralizing antibody responses in healthy adults. (ClinicalTrials.gov Identifiers: NCT00347672 and NCT00488046).

Vaccine
Volume 27, Issue 36, Pages 4875-5026 (6 August 2009)
http://www.sciencedirect.com/science/journal/0264410X

Trends in early childhood vaccination coverage: Progress towards US Healthy People 2010 goals
Pages 5008-5012
Zhen Zhao, Philip J. Smith, Elizabeth T. Luman

Abstract
Objectives
To evaluate trends in national vaccination coverage from 2000 to 2007 among children aged 19–35 months for at least four doses of diphtheria–tetanus–pertussis vaccine (4 + DTaP), three doses of poliovirus vaccine (3 + Polio), one dose of measles–mumps–rubella vaccine (1 + MMR), three doses of Haemophilus influenzae type b vaccine (3 + Hib), three doses of hepatitis B vaccine (3 + HepB), one dose of Varicella vaccine (1 + Var), and the standard vaccine series of these six vaccines (4:3:1:3:3:1). To predict vaccination coverage levels in 2008–2010 for those vaccines that have not yet reached the Healthy People 2010 coverage targets of 90% for individual vaccines and 80% for the vaccine series.

Methods
Data were analyzed for 167,086 children aged 19–35 months in the 2000–2007 National Immunization Survey. Vaccination coverage trends were analyzed with weighted least squares linear regression models. Nonlinear Weibull and logarithmic regression models were fitted to these past results, and extrapolation was used to predict vaccination coverage levels for 4 + DTaP, 1 + Var, and the 4:3:1:3:3:1 series from 2008 to 2010.

Results
From 2000 to 2007, observed vaccination coverage increased significantly for four of the six vaccines and the standard vaccine series, and reached the 90% target for 3 + Polio, 1 + MMR, 3 + Hib, and 3 + HepB. Increases in coverage were not significant for 1 + MMR and 3 + Hib; however, coverage for these vaccines was consistently > 90% throughout the study period. Both Weibull and logarithmic regression models predicted that coverage with 1 + Var and the 4:3:1:3:3:1 series will surpass the 2010 target by 2008, while coverage with 4 + DTaP will fall short of the target at 86% in 2010.

Conclusions
The United States is well on the way toward reaching most of the Healthy People 2010 objectives for early childhood vaccination coverage. Enhanced efforts are needed to ensure that these trends continue, and to increase coverage with 4 + DTaP.

Volume 27, Issue 35, Pages 4739-4874 (30 July 2009)

http://www.sciencedirect.com/science?_ob=PublicationURL&_tockey=%23TOC%235188%232009%23999729964%231320081%23FLA%23&_cdi=5188&_pubType=J&_auth=y&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=6e0bab7329320967a8de11d8a69c04bb

Vaccine
Volume 27, Issue 36, Pages 4875-5026 (6 August 2009)
http://www.sciencedirect.com/science/journal/0264410X

Is routine influenza immunization warranted in early pregnancy?
Pages 4754-4770
Danuta M. Skowronski, Gaston De Serres

Abstract
Routine influenza immunization is recommended for select groups because of their higher risk of serious influenza outcomes. Based on that benefit–risk framework, we assessed whether routine administration of trivalent inactivated influenza vaccine (TIV) is warranted in pregnancy, beginning in 1st trimester. Higher maternal mortality due to influenza was extensively described during the 1918 and 1957 pandemics, but epidemiologic evidence thereafter is limited to case reports and a single ecologic analysis during a single season. Significantly elevated rates of hospitalization have been reported with seasonal influenza beginning in 1st trimester among women with select comorbidities and during the 2nd half of normal pregnancy. TIV protection against serious outcomes in pregnant women has not yet been shown. Although harm has also not been shown, sample size to date is insufficient to assert TIV safety in 1st trimester. Benefit–risk analysis suggests influenza immunization may be warranted at any stage of pregnancy during certain pandemics and annually among women with select comorbidities. TIV may also be warranted to protect women against influenza-related hospitalization during the 2nd half of normal pregnancy. Evidence is otherwise insufficient to recommend routine TIV as the standard of practice for all healthy women beginning in early pregnancy.

Vaccine
Volume 27, Issue 36, Pages 4875-5026 (6 August 2009)
http://www.sciencedirect.com/science/journal/0264410X

Interpretation of primary care physicians’ attitude regarding rotavirus immunisation using diffusion of innovation theories
Pages 4771-4775
Philipp Agyeman, Daniel Desgrandchamps, Bernard Vaudaux, Christoph Berger, Alessandro Diana, Ulrich Heininger, Claire-Anne Siegrist, Christoph Aebi

Abstract
To evaluate primary care physicians’ attitude towards implementation of rotavirus (RV) immunisation into the Swiss immunisation schedule, an eight-question internet-based questionnaire was sent to the 3799 subscribers of InfoVac, a nationwide web-based expert network on immunisation issues, which reaches >95% of paediatricians and smaller proportions of other primary care physicians. Five demographic variables were also inquired. Descriptive statistics and multivariate analyses for the main outcome “acceptance of routine RV immunisation” and other variables were performed. Diffusion of innovation theory was used for data assessment. Nine-hundred seventy-seven questionnaires were returned (26%). Fifty percent of participants were paediatricians. Routine RV immunisation was supported by 146 participants (15%; so called early adopters), dismissed by 620 (64%), leaving 211 (21%) undecided. However, when asked whether they would recommend RV vaccination to parents if it were officially recommended by the federal authorities and reimbursed, 467 (48.5%; so called early majority) agreed to recommend RV immunisation. Multivariate analysis revealed that physicians who would immunise their own child (OR: 5.1; 95% CI: 4.1–6.3), hospital-based physicians (OR: 1.6; 95% CI: 1.1–2.3) and physicians from the French (OR: 1.6; 95% CI: 1.2–2.3) and Italian speaking areas of Switzerland (OR: 2.5; 95% CI: 1.1–5.8) were more likely to support RV immunisation. Diffusion of innovation theory predicts a >80% implementation if approximately 50% of a given population support an innovation. Introduction of RV immunisation in Switzerland is likely to be successful, if (i) the federal authorities issue an official recommendation and (ii) costs are covered by basic health care insurance.

Vaccine
Volume 27, Issue 36, Pages 4875-5026 (6 August 2009)
http://www.sciencedirect.com/science/journal/0264410X

Cost-effectiveness of prophylactic vaccination against human papillomavirus 16/18 for the prevention of cervical cancer: Adaptation of an existing cohort model to the situation in the Netherlands
Pages 4776-4783
R.M. Rogoza, T.A. Westra, N. Ferko, J.J. Tamminga, M.F. Drummond, T. Daemen, J.C. Wilschut, M.J. Postma

Abstract
Cervical cancer is one of the most prevalent cancers among women worldwide. Implementation of an HPV-vaccination strategy targeting the major oncogenic types 16 and 18 that cause cervical cancer is generally expected to significantly reduce the burden of cervical cancer disease. Here we estimate the costs, savings and health gains with the addition of HPV-16/18 vaccination to the already existing Dutch screening programme. In the base-case analysis, it was estimated that implementation of an HPV-16/18 vaccine would result in an incremental cost-effectiveness ratio (ICER) of €22,700 per life-year gained (LYG). In sensitivity analysis, the robustness of our finding of favourable cost-effectiveness was established. The ICER appeared sensitive to the vaccine price, discount rate and duration of vaccine-induced protection. From our results, it validly follows that immunization of 12-year-old Dutch girls against HPV-16/18 infection is a cost-effective strategy for protecting against cervical cancer.

The WHO continues to issue regular updates on both A/(H1N1) and A/(H5N1) posted on the WHO main page, as well as other advisories linked from that page. Here are the current updates:

– Pandemic (H1N1) 2009 – update 58

6 July 2009 – The title of this update has now evolved to “Pandemic (H1N1) 2009.” WHO notes 94,512 officially reported cases of influenza A(H1N1) infection (up from 59,814 a week ago and 44,287 a week earlier), including 429 deaths (up from 263 a week ago and 180 a week earlier). [no update to 6 July report published as of 11 July 2009: 06.25]

http://www.who.int/csr/don/2009_07_06/en/index.html

WHO has included an interactive “timeline of all cases” (requires Flash player) at:

http://gamapserver.who.int/h1n1/atlas.html?select=ZZZ&filter=filter4,confirmed

– Pandemic (H1N1) 2009 briefing note 1

Viruses resistant to oseltamivir (Tamiflu) identified

8 July 2009 – [full text]

WHO said it has been informed by health authorities in Denmark, Japan and the Special Administrative Region of Hong Kong, China of the appearance of H1N1 viruses which are resistant to the antiviral drug oseltamivir (known as Tamiflu) based on laboratory testing. These viruses were found in three patients who did not have severe disease and all have recovered. Investigations have not found the resistant virus in the close contacts of these three people. The viruses, while resistant to oseltamivir, remain sensitive to zanamivir.

WHO said that close to 1000 pandemic H1N1 viruses have been evaluated by the laboratories in the Global Influenza Surveillance Network for antiviral drug resistance. All other viruses have been shown sensitive to both oseltamivir and zanamivir. WHO and its partners will continue to conduct ongoing monitoring of influenza viruses for antiviral drug resistance.

Therefore, based on current information, these instances of drug resistance appear to represent sporadic cases of resistance. At this time, there is no evidence to indicate the development of widespread antiviral resistance among pandemic H1N1 viruses. Based on this risk assessment, there are no changes in WHO’s clinical treatment guidance. Antiviral drugs remain a key component of the public health response when used as recommended.

http://www.who.int/csr/disease/swineflu/notes/h1n1_antiviral_resistance_20090708/en/index.html

– Cumulative Number of Confirmed Human Cases of Avian Influenza A/(H5N1) Reported to WHO

1 July 2009  [No update since 1 July 2009]

The published tabular chart reports 436 confirmed cases (up from 433 cases reported as of 2 June 2009) and 262 deaths (unchanged from the 2 June 2009 report).

http://www.who.int/csr/disease/avian_influenza/country/cases_table_2009_06_02/en/index.html

The Weekly Epidemiological Record (WER) for 10 July 2009, vol. 84, 28 includes: Progress towards poliomyelitis eradication in India, January 2007–May 2009; New influenza A (H1N1) virus – update http://www.who.int/wer/2009/wer8428.pdf

HHS Secretary Kathleen Sebelius discussed early stage planning for Pandemic H1N1 vaccination later this year noting that some vaccine may be available for distribution by October. HHS said its advisory committees is reviewing which population groups may be offered vaccine and in what priority, but said that “…young people have been disproportionately impacted by this virus, and we anticipate that school-aged children, non-elderly adults with underlying health conditions, pregnant women, and healthcare and emergency workers who are likely to come in contact with the virus will be priority groups to whom vaccine will be offered.” The National Institute of Allergy and Infectious Diseases (NIAID) hopes to evaluate the first candidate H1N1 vaccine in early August.

CIDRAP: http://www.cidrap.umn.edu/cidrap/content/influenza/swineflu/news/jul0909summit-jw.html

HHS Secretary Kathleen Sebelius announced the availability of $350 million in grants to help states and territories prepare for the 2009 novel H1N1 flu virus and the fall flu season. The grants were funded by the recent supplemental appropriations bill that was passed by Congress and signed into law by President Barack Obama on June 24, 2009. Secretary Sebelius said, “With flu season around the corner, we must remain vigilant and do all we can to prepare our nation and protect public health. These grants will give states valuable resources to step up their flu preparedness efforts.” A total of US$260 million in Public Health Emergency Response Grants will “help state public health departments perform a variety of functions, including preparing for potential vaccination campaigns, implementing strategies to reduce people’s exposure to the 2009 novel H1N1 flu and improving influenza surveillance and investigations.” Some US$90 million in Hospital Preparedness grants will be distributed to “enhance the ability of hospitals and health care systems to prepare for and respond to public health emergencies. Local outbreaks of the novel H1N1 virus have produced a surge of patients at hospitals, and these grants will help ensure hospitals are ready for future outbreaks that may impact their community.”

http://www.flu.gov/whereyoulive/flugrants_20090710.html

http://www.businesswire.com/portal/site/home/permalink/?ndmViewId=news_view&newsId=20090710005558&newsLang=en

The IFPMA (International Federation of Pharmaceutical Manufacturers & Associations) said it was invited to attend a special session of the United Nations (UN) in Geneva on health in Africa and other least developed countries, organized by the UN Economic and Social Commission (ECOSOC). Michael D. Boyd, Acting Director General of the IFPMA, gave “a briefing on the research-based pharmaceutical industry’s contribution to improving health in the developing world, speaking to an audience which included foreign ministers of UN Member States and senior UN officials.”  Mr. Boyd commented, “A quiet transformation has been going on over the last decade or so, strengthening links between the developed world and least developed countries, especially in the area of health. As a single industry sector, the IFPMA’s member companies have made an unprecedented contribution to improving health in the countries which have the greatest needs.” IFPMA said that since the inception of the UN Millennium Development Goals, through to the end of 2007, “IFPMA member companies made available enough medical assistance to reach nearly 2 billion people in low and middle income countries – assistance conservatively valued at USD 9.2 billion.” Further details are available at  www.ifpma.org/healthpartnerships Geneva, 8 July 2009

http://www.ifpma.org/News/NewsReleaseDetail.aspx?nID=12402

JAMA
Vol. 302 No. 2, pp. 121-216, July 8, 2009
http://jama.ama-assn.org/current.dtl

Original Contribution
Effect of Reduced-Dose Schedules With 7-Valent Pneumococcal Conjugate Vaccine on Nasopharyngeal Pneumococcal Carriage in Children
A Randomized Controlled Trial

Elske J. M. van Gils, MD; Reinier H. Veenhoven, MD, PhD; Eelko Hak, PhD; Gerwin D. Rodenburg, MD; Debby Bogaert, MD, PhD; Ed P. F. IJzerman, MD, PhD; Jacob P. Bruin; Loek van Alphen, PhD; Elisabeth A. M. Sanders, MD, PhD

JAMA. 2009;302(2):159-167.

Context  The effects of reduced-dose schedules of 7-valent pneumococcal conjugate vaccine (PCV-7) on pneumococcal carriage in children are largely unknown, although highly relevant in the context of subsequent herd effects.

Objective  To examine the effects of a 2-dose and 2 + 1-dose PCV-7 schedule on nasopharyngeal pneumococcal carriage in young children compared with controls.

Design, Setting, and Patients  A randomized controlled trial of nasopharyngeal carriage of Streptococcus pneumoniae enrolling 1003 healthy newborns and 1 of their parents in a general community in the Netherlands, with follow-up to age 24 months and conducted between July 7, 2005, and February 14, 2008.

Intervention  Infants were randomly assigned to receive 2 doses of PCV-7 at 2 and 4 months; 2 + 1 doses of PCV-7 at 2, 4, and 11 months; or no dosage (control group).

Main Outcome Measure  Vaccine serotype pneumococcal carriage rates in infants in the second year of life.

Results  At 12 months, vaccine serotype pneumococcal carriage was significantly decreased after both PCV-7 schedules, with vaccine serotype pneumococcal carriage rates of 25% (95% confidence interval [CI], 20%-30%) and 20% (95% CI, 16%-25%) in the 2-dose and 2 + 1-dose schedule groups, respectively, vs 38% (95% CI, 33%-44%) in the control group (both P < .001). At 18 months, in the 2 + 1-dose schedule group, vaccine serotype pneumococcal carriage had further decreased to 16% (95% CI, 12%-20%) and, at 24 months, to 14% (95% CI, 11%-18%; both P < .001); whereas in the 2-dose schedule group, vaccine serotype pneumococcal carriage had remained stable at 18 months (24%; 95% CI, 20%-29%), but at 24 months had further decreased to 15% (95% CI, 11%-19%; both P < .001). In the control group, vaccine serotype pneumococcal carriage remained around 36% to 38% until 24 months.

Conclusion  Compared with no pneumococcal vaccination, a 2 + 1-dose and 2-dose schedule of PCV-7 resulted in significant reductions of vaccine serotype pneumococcal carriage in the second year of life.

Trial Registration  clinicaltrials.gov Identifier: NCT00189020

Author Affiliations: Department of Pediatric Immunology and Infectious Diseases, Wilhelmina Children’s Hospital (Drs van Gils, Hak, Rodenburg, Bogaert, and Sanders), and Julius Center for Health Sciences and Primary Care (Dr Hak), University Medical Center Utrecht, Utrecht; Department of Pediatrics, Spaarne Hospital, Hoofddorp (Drs van Gils, Veenhoven, and Rodenburg); Department of Epidemiology, University Medical Center Groningen, Groningen (Dr Hak); Regional Laboratory of Public Health, Haarlem (Dr IJzerman and Mr Bruin); and Netherlands Vaccine Institute, Bilthoven (Dr van Alphen), the Netherlands.

New England Journal of Medicine
Volume 361 — July 9, 2009 — Number 2
http://content.nejm.org/current.shtml

Perspective
Managing and Reducing Uncertainty in an Emerging Influenza Pandemic
M. Lipsitch and Others

[First 110 words per NEJM convention]
The early phases of an epidemic present decision makers with predictable challenges1 that have been evident as the current novel influenza A (H1N1) virus has spread. The scale of the problem is uncertain when a disease first appears but may increase rapidly. Early action is required, but decisions about action must be made when the threat is only modest — and consequently, they involve a trade-off between the comparatively small, but nearly certain, harm that an intervention may cause (such as rare adverse events from large-scale vaccination or economic and social costs from school dismissals) and the uncertain probability of . .

Science
10 July 2009  Vol 325, Issue 5937, Pages 117-232
http://www.sciencemag.org/current.dtl

News of the Week
Scientific Community:
Resignations Highlight Disagreement On Vaccines in Autism Group
Erik Stokstad

A prominent member of the science advisory board for Autism Speaks, the largest private funder of autism research, resigned last week citing his disagreement with efforts to study vaccines as a possible cause of autism. Eric London, a psychiatrist and chief science advisor for the New York State Autism Consortium, says that funding such research, in addition to being wasteful, unduly heightens parents’ concerns about the safety of immunization. London’s departure is a sign of growing frustration in the research community, says Alison Singer, a former high-ranking leader of Autism Speaks who resigned from the group in January.

Vaccine
Volume 27, Issue 34, Pages 4551-4738 (23 July 2009)
http://www.sciencedirect.com/science/journal/0264410X

Regular Papers
A new, rapid, and promising approach to aerosol immunization: Inflatable bags and valved masks
Pages 4571-4575
John V. Bennett, Jorge Fernandez de Castro, Roberto Martinez Poblete, Maria Luisa Garcia Alcantara, Esperanza Gallardo Diaz, Miguel Angel Molina Angeles, Rosa Maria Wong Chew, Eloisa Arias Toledo, Clyde Witham, Jose Ignacio Santos Preciado

Abstract
Booster doses of MMR vaccine equal in dosage to injected doses were aerosolized into a 3/4 l bag that inflated in 4 s. The bag was then attached to valved masks, and its contents rapidly inhaled in one or two deep breaths by preschool Mexican children. Antibody responses in the children exposed to the aerosolized measles component were superior to those noted after injection, while responses to the mumps and rubella components were equivalent. The new method appears to be effective, safe, and has several advantages over previously used methods. Further explorations of the approach seem merited.

Vaccine
Volume 27, Issue 34, Pages 4551-4738 (23 July 2009)
http://www.sciencedirect.com/science/journal/0264410X

Regular Papers
Transmission-dynamic model to capture the indirect effects of infant vaccination with Prevnar (7-valent pneumococcal conjugate vaccine (PCV7)) in older populations

Pages 4694-4703
Sonya J. Snedecor, David R. Strutton, Vincent Ciuryla, Elissa J. Schwartz, Marc F. Botteman

Abstract
We developed an age-structured, transmission-dynamic, mathematical model to quantify the direct and indirect benefits of infant PCV7 vaccination. The model simulates the acquisition of asymptomatic carriage of Streptococcus pneumoniae and the development of fatal and non-fatal invasive pneumococcal disease (IPD) among vaccinated and unvaccinated individuals aged <2, 2–4, 5–17, 18–49, 50–64, and ≥65 years old. The model was parameterized using published US surveillance data, supplemented with data from published literature. The model predicts the observed incidence of IPD with good agreement and may be used to predict the impact of various vaccination strategies in the US or other populations yet to introduce PCV7.

Vaccine
Volume 27, Issue 34, Pages 4551-4738 (23 July 2009)
http://www.sciencedirect.com/science/journal/0264410X

Regular Papers
Which determinants should be targeted to increase influenza vaccination uptake among health care workers in nursing homes?
Pages 4724-4730
I. Looijmans-van den Akker, J.J.M. van Delden, Th.J.M. Verheij, G.A. van Essen, M.A.B. van der Sande, M.E. Hulscher, E. Hak

Abstract

Although health care workers (HCWs) have been recommended to be immunized against influenza, vaccine uptake remains low. So far, research on determinants of influenza vaccination among HCWs has been limited by design, population or theoretical framework. Therefore we conducted a questionnaire study in Dutch nursing homes to assess which demographical, behavioural and organisational determinants were associated with influenza vaccine uptake among HCWs. We were able to accurately predict vaccine uptake based on a 13-item prediction model including two demographical, nine behavioural and two organisational determinants developed with data from 1,125 respondents (response rate 60%). To further increase influenza vaccine uptake, implementation programs should target these determinants.