Sunday, September 27, 2009

New Guidelines Recommend Revaccinating Those at Prolonged Increased Risk for Meningococcal Disease

From Medscape Medical News
Laurie Barclay, MD

September 25, 2009 — The Advisory Committee on Immunization Practices (ACIP) has updated and replaced its previous recommendations for revaccinating persons at prolonged increased risk for meningococcal disease. The new guidelines, which were approved at the June 24, 2009, ACIP meeting, are published in the September 25 issue of the Morbidity and Mortality Weekly Report.

ACIP has previously recommended quadrivalent meningococcal conjugate vaccine (MCV4; Menactra, Sanofi Pasteur) for all persons aged 11 to 18 years, as well as for persons aged 2 to 55 years who are at increased risk for meningococcal disease. Although MCV4 is licensed as a single dose, ACIP now recommends that persons at increased risk for meningococcal disease for prolonged periods of time because of medical conditions or because of prolonged exposure should be revaccinated with MCV4 every 5 years.

"Because of the high risk for meningococcal disease among certain groups and limited data on duration of protection, at its June 2009 meeting ACIP recommended that persons previously vaccinated with either MCV4 or MPSV4 (Menomune, Sanofi Pasteur) who are at prolonged increased risk for meningococcal disease should be revaccinated with MCV4," writes ACIP's Meningococcal Vaccine Work Group. "Persons who previously were vaccinated at age ≥7 years and are at prolonged increased risk should be revaccinated 5 years after their previous meningococcal vaccine, and persons who previously were vaccinated at ages 2–6 years and are at prolonged increased risk should be revaccinated 3 years after their previous meningococcal vaccine.... Persons who remain in one of these increased risk groups indefinitely should continue to be revaccinated at 5-year intervals."

Conditions placing persons at prolonged increased risk for meningococcal disease include persistent complement component deficiencies (such as C3, properdin, Factor D, and late complement component deficiencies), anatomic or functional asplenia, and prolonged exposure (eg, microbiologists routinely working with Neisseria meningitidis, or travelers to or residents of countries where meningococcal disease is hyperendemic or epidemic).

At this time, it is not recommended that college freshmen who live in dormitories but who were previously vaccinated with MCV4 be revaccinated. However, college freshmen who live in dormitories and who were vaccinated with MPSV4 5 or more years previously should be vaccinated with MCV4.

The new recommendations from ACIP's Meningococcal Vaccine Work Group are based on a review of data on the risk for meningococcal disease, decrease in antibody titer, and the safety and immunogenicity of revaccination with MCV4 at 3 and 5 years after the first dose of MCV4 or MPSV4.

Higher levels of serum bactericidal antibody against N meningitidis can offer increased protection to persons with prolonged increased risk for meningococcal disease. All persons revaccinated with MCV4 in the reviewed studies reached serum bactericidal antibody titers greater than 1:128 for serogroups C and Y. About 50% to 70% of persons in previously vaccinated and in unvaccinated groups reported mild to moderate local and systemic adverse events after revaccination or initial vaccination with MCV4, but no serious adverse events were reported in either group.

"On the basis of these data, expert opinion of the workgroup members, and feedback from partner organizations, the workgroup proposed that persons at prolonged increased risk for meningococcal disease be revaccinated with MCV4," the ACIP Meningococcal Vaccine Work Group writes. "Although the duration of protection from MCV4 is unknown, most entering college students will have received MCV4 within the preceding 4 years. Because of the limited period of increased risk, ACIP currently does not recommend that college freshmen living in dormitories who were previously vaccinated with MCV4 be revaccinated."

Information regarding MCV4 and other recommendations for individuals aged 2 to 55 years has been published previously. This includes a routine recommendation that persons aged 11 to 18 years be vaccinated with MCV4.

Morb Mortal Wkly Rep. 2009:58;1042–1043.

Live Attenuated Flu Vaccine May Be Less Effective Than Inactivated Flu Vaccine

From Medscape Medical News
Laurie Barclay, MD

September 24, 2009 — During the 2007–2008 flu season, the inactivated influenza vaccine (injection) was more effective than the live attenuated vaccine (intranasal spray) in preventing laboratory-confirmed symptomatic influenza A (mostly H3N2) in healthy adults. However, both vaccines prevented influenza illnesses, according to the results of a randomized, double-blind, placebo-controlled trial reported in the September 24 issue of the New England Journal of Medicine.

"The efficacy of influenza vaccines may vary from year to year, depending on a variety of factors, and may differ for inactivated and live attenuated vaccines," write Arnold S. Monto, MD, from the University of Michigan School of Public Health in Ann Arbor, and colleagues. "Influenza-related morbidity was high in 2007–2008, a year in which type A (H3N2) viruses predominated; these viruses were characterized by a slight antigenic drift from the type A (H3N2) viral strain included in the vaccine."

This trial compared the estimated absolute and relative efficacies of licensed inactivated and live attenuated influenza vaccines in 1952 healthy adults who received study vaccines in the fall of 2007. Influenza activity was documented from January through April 2008, with influenza types A (H3N2) accounting for about 90% of circulating virus and type B for about 9%.

Absolute efficacy was determined by isolating the virus in culture, identifying it on real-time polymerase-chain-reaction assay, or both. For the inactivated vaccine, absolute efficacy was 68% (95% confidence interval [CI], 46% – 81%) compared with 36% (95% CI, 0% – 59%) for the live attenuated vaccine. Estimates of relative efficacy showed that for participants who received inactivated vaccinethere was a 50% (95% CI, 20% – 69%) reduction in laboratory-confirmed influenza compared with those who received live attenuated vaccine.

Against the influenza A virus, absolute efficacy was 72% (95% CI, 49% – 84%) for the inactivated vaccine and 29% (95% CI, −14% to 55%) for the live attenuated vaccine, yielding a relative efficacy of 60% (95% CI, 33% – 77%) for the inactivated vaccine.

"In the 2007–2008 season, the inactivated vaccine was efficacious in preventing laboratory-confirmed symptomatic influenza A (predominately H3N2) in healthy adults," the study authors write. "The live attenuated vaccine also prevented influenza illnesses but was less efficacious."

Limitations of this study include lack of conclusive evidence to date regarding the efficacy of the 2 vaccines for the influenza B viruses.

"We are entering a new era of influenza control, one in which different types of vaccines may be appropriate for different age groups," the study authors conclude. "In preliminary testing of prevaccination and postvaccination serum samples collected as part of the current study, a small proportion of the participants who received the inactivated vaccine in the fall of 2007 had antibody responses to the novel virus, but none of the recipients of the live attenuated vaccine had a similar response. Ideally, data from direct comparison of the vaccines will be made available to inform the choices that will be required as we go forward into relatively uncharted territory."

N Engl J Med. 2009;361:1260–1267.

Saturday, September 26, 2009

Severe H1N1 Infection in Children Linked to Asthma and Other Diseases

From Medscape Medical News
Barbara Boughton

September 17, 2009 (San Francisco, California) — Although most cases of H1N1 influenza are mild and self-limited, severe disease in children is most likely linked to underlying conditions such as asthma, according to Canadian research presented here at the 49th Interscience Conference on Antimicrobial Agents and Chemotherapy.

In the retrospective review, the case records of 89 children hospitalized with H1N1 were analyzed, and the researchers found that a "disturbing" number of children had serious complications requiring a stay in the intensive-care unit (ICU), said Bruce Tapiero, MD, from the Division of Infectious Diseases, Department of Pediatrics, CHU Sainte-Justine in Montreal, Quebec.

In the study, researchers identified 80 children, of the 89 cases reviewed, who were admitted to Sainte-Justine Hospital with confirmed H1N1, as defined by a positive PCR test. Most of the children hospitalized were older than 6 years, and many were school-aged.

One or more underlying medical conditions was found in 66% of the children, with the most common being asthma, sickle cell disease, and encephalopathy. Other underlying conditions were pneumonia and congenital heart disease.

Although most of the children displayed the usual features of H1N1 —fever, cough, and sore throat — a striking number also had gastrointestinal symptoms (49%). In fact, the 1 death that occurred from H1N1 was attributed to gastrointestinal complications, underlying lung disease, and encephalopathy.

Fever was seen in most of the children, and neurological features of the disease were common, with 7 children experiencing febrile seizures. In addition, 35% of the children had oxygen-saturation levels below 95%, and 4 of the sickest patients required mechanical ventilation.

Thirteen of the children (16%) required admission to the ICU, and most of those children had underlying comorbidities. The findings suggest that the infection might be particularly severe in these children, the investigators say. Despite the severity of illness, length of stay in the ICU was brief. Most of the children did not have extended stays in the hospital. The mean hospitalization for the group was 4 days.

The Canadian team noted that some lessons could be drawn from their study. Most children with H1N1, even those who are hospitalized, have moderate disease, they note. However, gastrointestinal symptoms and febrile seizures are prevalent in children with H1N1. Thus, it is important that clinicians pay attention to these symptoms when evaluating children for H1N1 to improve diagnosis and treatment, the researchers advise.

"This was a descriptive study, so it had some limitations," said Laurent Kaiser, MD, from University Hospital of Switzerland in Geneva, who moderated the session at which the study was presented. "But it shows us some interesting features of children with the most severe disease," he said.

"At the same time, we don't really have documentation about how widespread the disease is in children," Dr. Kaiser said. That kind of information can only come from large national studies, he explained. "What we're seeing here is the tip of the iceberg, but we don't really know the size of the iceberg yet because it's such a new disease."

49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC): Presentation V-1269d. Presented September 14, 2009.

Friday, September 25, 2009

Drug-Resistant 19A Serotype Causes Nearly Half of All Pediatric Invasive Pneumococcal Disease Cases

From Medscape Medical News
Barbara Boughton

September 22, 2009 (San Francisco, California) — An investigational 13-valent pneumococcal conjugate vaccine manufactured by Wyeth, currently under review by the US Food and Drug Administration (FDA), should help eliminate newly emerging drug-resistant pneumococcal strains.

Despite the success of the pediatric 7-valent pneumococcal conjugate vaccine (Prevnar, Wyeth) that was introduced in 2000, drug-resistant pneumococcal strains — particularly the 19A serotype — have emerged and threaten the health of some children, particularly those 2 to 4 years of age with underlying health conditions. These children might benefit from catch-up immunizations with the 13-valent vaccine, pending approval, according to 2 teams of researchers here at the 49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC).

"We are at the point where we've already reduced 80% of the disease burden," said Pekka Nuorti, MD, DSc, from the Respiratory Disease Branch of the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, which sponsored one of the studies. "But we wanted to see how much of the remaining disease is vaccine-preventable."

In their study, the CDC researchers assessed the number of cases of invasive pneumococcal disease (IPD) in 2007 and identified the isolates from these cases.

They found that 64% of the estimated 5040 cases of IPD were caused by serotypes targeted by the new 13-valent vaccine, whereas only 2% were caused by serotypes contained in the currently used vaccine. Serotype 19A accounted for 42% of cases.

The 13-valent vaccine "has the potential to substantially reduce the remaining [pneumococcal] disease burden," Dr. Nuorti said in an interview with Medscape Infectious Diseases. "It looks like there might be some groups that might benefit from a catch-up immunization — including older children with underlying medical conditions."When it makes its recommendations for the vaccine, the CDC will also consider a catch-up vaccination strategy for all children 2 to 4 years of age to extend the vaccine's protection to unvaccinated groups, he said. The vaccine is expected to be licensed by the FDA later this year or early next year.

In another study presented here at the ICAAC, researchers from University Hospitals Case Medical Center in Cleveland, Ohio assessed isolates from 171 cases of Streptococcus pneumonias at their institution in 2008.

Nonvaccine serotypes predominated, and 19A was the most commonly isolated serotype, accounting for about a third of all cases.

"There's been an incredible increase in nonvaccine serotypes and most of that increase is due to 19A," said lead researcher Michael R Jacobs, MD, PhD, director of pathology and medicine at Case Western Reserve University in Cleveland. "No one really predicted this when the [7-valent] vaccine was first introduced," Dr. Jacobs said in an interview with Medscape Infectious Diseases. "Some scientists hypothesized that serotype 19F, which is contained in the 7-valent vaccine, might provide cross-protection against 19A, but that hasn't proved to be the case," Dr. Jacobs added.

In the Cleveland study, most of the nonvaccine isolates, particularly 19A, were resistant to many antibiotics, including penicillin, amoxicillin, ceftriaxone, azithromycin, and clindamycin. "This [increase in nonvaccine isolates] may well represent a trend of replacement serotypes and increasing invasiveness and drug nonsusceptibility, and bears careful watching," the authors conclude in their study.

Although agreeing that the 7-valent vaccine has reduced the morbidity and mortality burden from pneumococcal disease, other researchers consider the growth in drug-resistant replacement serotypes a concern.

"The routine use of hepavalent pneumococcal vaccine [PCV 7] has substantially reduced the rate of invasive pneumococcal disease in children and in the general population," said Luke Chen, MBBS, FRACP, assistant professor of medicine in the Division of Infectious Diseases at Duke University Medical Center in Durham, North Carolina. "However, many investigators have also described an increase in the rate of IPDs caused by serotypes of pneumococci that were not included in PCV 7 — a phenomenon known as 'serotype replacement'," Dr. Chen said.

"The evolving epidemiology of pneumococci is of interest because some nonvaccine serotype pneumococci, such as 19A, are associated with increasing antimicrobial resistance. Other nonvaccine serotypes, such as serotypes 1 and 5, are associated with higher rates of invasive pulmonary disease, such as empyemas and parapneumonic effusions," Dr. Chen added.

The results of the Cleveland study presented by Dr. Jacobs and colleagues are alarming because more than 70% of all serotype 19A isolates were not susceptible to penicillin or ceftriaxone, according to Dr. Chen. "It remains unclear, however, whether the emergence of non-PCV 7 serotype pneumococci and increasing antimicrobial resistance are associated with excess mortality or morbidity," he added.

The CDC study's data are interesting because they project a substantial and further reduction in the overall rates of IPD after transitioning from PCV 7 to a 13-valent pneumococcal vaccine, Dr. Chen said. "PCV 13 may also reduce the incidence of serotypes that are associated with increasing antimicrobial resistance, such as 19A," he added.

Dr. Nuorti, Dr. Jacobs, and Dr. Chen have disclosed no relevant financial relationships.

49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC): Abstracts G1-1554 and G1-1536. Presented September 14, 2009.

Friday, September 18, 2009

Atopic Dermatitis - update on treatment

Pediatrics. 2008;122:812-824.

Clinical Context

AD affects 10% to 20% of children, according to Larsen and Hanifin in the February 2002 issue of Immunology and Allergy Clinics of North America. The primary factors in AD are epidermal barrier function defects and skin inflammation. The diagnosis of AD is based on combined essential, important, and associated nonspecific features. Essential features include pruritus, eczematous dermatitis, typical morphologic features with age-specific patterns, and chronic or relapsing nature.

This review of AD describes the management of AD, including topical corticosteroids, topical calcineurin inhibitors, and new treatments.

Study Highlights

Education is a crucial part of management:
A 6-week education program for parents resulted in improved quality of life and eczema severity for their children older than 12 months.
Comprehensive centers can provide care in dermatology, allergy, infectious disease, and behavioral psychology.

Trigger avoidance measures include mattress covers, low-pile carpet, pets that do not produce dander, and avoidance of known food allergens.
The American Academy of Pediatrics 2008 breast-feeding guidelines recommend exclusive breast-feeding for at least 4 months to decrease AD incidence in the first 2 years of life in children at high risk for AD.
There is no evidence that delaying solid food, including cow's milk, fish, eggs, and peanut-containing foods, after ages 4 to 6 months protects against AD.
Studies on probiotic effects on risk for AD had conflicting results.
Skin care recommendations include dye-free, fragrance-free emollients and moisturizers applied at least twice a day, ointments, and ceramide-rich products.
"510(k) medical devices" are approved by the US Food and Drug Administration as new barrier products.
Bathing in lukewarm water with moisturizing cleanser for several minutes once or twice a day should be followed by use of a towel to pat dry and emollients.
Avoid fragrance soaps or bubble baths.
First-line treatment of AD flares is topical corticosteroids:
Class I are most potent and class VII, least potent.
Adverse effects are skin atrophy, striae, telangiectasias, hypopigmentation, rosacea, perioral dermatitis, acne, cataracts, glaucoma, hypothalamic-pituitary-adrenal axis suppression, growth retardation, and bone density reduction.
Twice-a-day use has the same effect as once-a-day use.
The topical calcineurin inhibitors tacrolimus and pimecrolimus are second-line treatment for short-term and noncontinuous long-term use in immunocompetent patients at least 2 years old with moderate to severe AD:
Long-term safety is not known, according to 2006 US Food and Drug Administration boxed warning.
Indications include AD persistence or frequent flares requiring almost continuous topical corticosteroids and involvement of sensitive skin areas.
Sedating antihistamines hydroxyzine and diphenhydramine might improve sleep but do not directly affect AD-related pruritus.
Possible complications include overgrowth of S aureus, Molluscum contagiosum, eczema herpeticum, eczema vaccinatum, and fungal infections.
If bacterial superinfection occurs, culture for methicillin-resistant S aureus should be considered.
Diluted bleach baths can decrease local skin infections and need for systemic antibiotics.
Wet wraps and once-daily topical corticosteroids are effective for severe or refractory AD, but close supervision is needed because of risk for skin maceration or secondary infection.
Systemic immunomodulatory therapies can be used for refractory AD:
Multiple phototherapy sessions
Short-term cyclosporine; long-term use can be linked with hypertension and renal toxicity
Azathioprine monotherapy; monitor blood cell counts and liver function tests
Mycophenolate mofetil appears safe; prospective controlled studies are needed.
Dermatology referral indications include moderate or severe AD, poor response to moderate-potency topical corticosteroids, persistent AD, frequent flares, AD-related hospitalization, and systemic therapy.
Other specialty referrals include allergy referral for suspected specific triggers and gastroenterology or immunology referral for possible eosinophilic gastroenteritis or esophagitis with failure to thrive or frequent systemic infections.

Pearls for Practice

In children with atopic dermatitis, the first-line treatment is topical corticosteroids, with potency ranging from the least potent class VII to the most potent class I. Second-line treatment of frequent flares or sensitive skin areas is a topical calcineurin inhibitor, for use in children 2 years or older.
New treatment modalities for children with atopic dermatitis include education models; bleach bath; wet wraps; and systemic immunomodulatory therapies, including phototherapy, cyclosporine, azathioprine, and mycophenolate mofetil.

Monday, September 14, 2009

Nonadjuvanted Influenza Vaccines May Not Protect Against 2009 H1N1

From Medscape Medical News
Laurie Barclay, MD

September 11, 2009 — Recent seasonal nonadjuvanted influenza vaccines may not protect against pandemic H1N1 virus (2009 H1N1), according to the results of a study reported online September 10 issue in the New England Journal of Medicine.

"A new pandemic influenza A (H1N1) virus has emerged, causing illness globally, primarily in younger age groups," write Kathy Hancock, PhD, from the Influenza Division, National Center for Immunization and Respiratory Diseases, the Centers for Disease Control and Prevention, Atlanta, Georgia, and colleagues. "To assess the level of preexisting immunity in humans and to evaluate seasonal vaccine strategies, we measured the antibody response to the pandemic virus resulting from previous influenza infection or vaccination in different age groups."

The investigators used a microneutralization assay to quantify titers of antibodies cross-reactive to 2009 H1N1 in stored serum samples from individuals who either donated blood or who received recent seasonal or 1976 swine influenza vaccines.

Preexisting cross-reactive antibody titers of 40 or more against 2009 H1N1 were present in 4 (4%) of 107 persons born after 1980. In contrast, 39 (34%) of 115 persons born before 1950 had titers of 80 or more.

The level of cross-reactive antibody to 2009 H1N1 increased by 4-fold or greater after receipt of seasonal trivalent inactivated influenza vaccines in none of 55 children aged 6 months to 9 years, in 12% to 22% of 231 adults aged 18 to 64 years, and in 5% or less of 113 adults aged 60 years or older. Cross-reactive antibody responses were not improved by seasonal vaccines formulated with adjuvant. In adults, administration of the A/New Jersey/1976 swine influenza vaccine substantially increased cross-reactive antibodies to 2009 H1N1.

"Vaccination with recent seasonal nonadjuvanted influenza vaccines induced little or no cross-reactive antibody response to 2009 H1N1 in any age group," the study authors write. "Persons under the age of 30 years had little evidence of cross-reactive antibodies to the pandemic virus. However, a proportion of older adults had preexisting cross-reactive antibodies."

Limitations of this study include the relatively small number of samples from pediatric trials.

"It remains clear that optimal protection against 2009 H1N1 in persons of all ages will be achieved with the development of a strain-specific pandemic vaccine," the study authors write. "Whether a one-dose or a two-dose vaccine regimen is needed to adequately immunize various age groups and whether the use of adjuvants will broaden the immune response against 2009 H1N1 if drifted strains emerge or provide dose-sparing benefits will ultimately be determined by the results of clinical studies that are now underway."

N Engl J Med. Published online September 10, 2009.

ACIP Updates Recommendations for Routine Poliovirus Vaccination

From Medscape Medical News
Laurie Barclay, MD

August 7, 2009 — The Advisory Committee on Immunization Practices (ACIP) has updated its recommendations for routine poliovirus vaccination and published them in the August 7 issue of the Morbidity and Mortality Weekly Report.

The goals of the update are to highlight the importance of the booster dose in children older than 4 years, to extend the minimum interval between dose 3 and dose 4 from 4 weeks to 6 months, to include a new precaution regarding use of minimum intervals in the first 6 months of life, and to recommend schedules for poliovirus vaccination with specific combination vaccines.

"On June 17, 1999, ACIP recommended that all poliovirus vaccine administered in the United States be an inactivated poliovirus vaccine (IPV) beginning January 1, 2000," the report states. "This policy was implemented to eliminate the risk for vaccine-associated paralytic poliomyelitis, a rare condition that has been associated with use of the live oral poliovirus vaccine.... Since 1999, no [oral poliovirus vaccine] has been distributed in the United States."

The 1999 ACIP recommendations specified a routine IPV vaccination schedule of 4 doses given at ages 2 months, 4 months, 6 to 18 months, and 4 to 6 years, with 4 weeks being the minimum interval between all IPV doses. In the United States, 3 different combination vaccines containing IPV have been licensed for routine use since the 2000 ACIP recommendation was made in1999.

The updated ACIP guidelines now include the following recommendations to avoid potential confusion related to using different vaccine products for routine and catch-up immunization:

The 4-dose IPV series should still be given at ages 2 months, 4 months, 6 to 18 months, and 4 to 6 years.
Regardless of the number of previous doses, the final dose in the IPV series should be given at age older than 4 years.
Between dose 3 and dose 4, the minimum interval is increased from 4 weeks to 6 months.
Between dose 1 and dose 2, and between dose 2 and dose 3, the minimum interval is still 4 weeks.
For dose 1, the minimum age is still 6 weeks.

Another new ACIP recommendation is that use of the minimum age and minimum intervals for vaccination in the first 6 months of life are recommended only if the vaccine recipient is at risk for imminent exposure to circulating poliovirus; for example, during an outbreak or for travel to a polio-endemic region. The rationale for this new precaution is that shorter intervals and earlier start dates result in lower seroconversion rates.

ACIP is also recommending a poliovirus vaccination schedule with specific combination vaccines, as follows:

When DTaP-IPV/Hib (Pentacel, Sanofi Pasteur) is given at ages 2, 4, 6, and 15 to 18 months (4 doses total), children should receive an additional booster dose of age-appropriate IPV-containing vaccine (IPV [Ipol, Sanofi Pasteur] or DTaP-IPV [Kinrix, GlaxoSmithKline]) at age 4 to 6 years, resulting in a 5-dose IPV vaccine series.

The booster dose at age 4 to 6 years should not be DTaP-IPV/Hib.

For optimal booster response, the minimum interval between dose 4 and dose 5 should be at least 6 months.
As per current recommendations, a booster dose should be given as soon as feasible to a child missing an IPV dose at age 4 to 6 years.

Morb Mortal Wkly Rep. 2009;58:829–830.

Fully Vaccinated Kids Still Get Chickenpox During Outbreak

From Reuters Health Information

(Reuters Health) Aug 12 - During an outbreak of varicella in an elementary school in Arkansas, students who were vaccinated once or twice still came down with the illness, though their symptoms were mild.

Furthermore, vaccine effectiveness was no better among those who received two inoculations prior to the outbreak than those who received only one, researchers report in the Pediatric Infectious Disease Journal for August.

"As our understanding of the effectiveness of one dose of varicella has developed (with) postlicensure studies, additional studies will be needed to assess the impact of the routine two-dose recommendation by the ACIP (Advisory Committee on Immunization Practices)," lead author Dr. Philip L. Gould and his associates write.

In June 2006, the ACIP recommended a second dose of varicella vaccine for children at age of school-entry and a catch-up second dose for all ages. According to the authors, an outbreak of chickenpox at the school in Arkansas was the first chance to investigate the effectiveness of this second dose. They note that the outbreak was the largest reported in recent years in the US.

Children were considered vaccinated if their first or second dose was received at least 42 days before rash onset. Among children with no history of varicella, vaccination coverage was 97% for at least one dose and 39% for the second dose. In addition, the report indicates, 15% had a positive history for varicella.

There were 84 cases of varicella between September 1 and December 18. Twenty-five cases had received two doses, 53 had received one dose, and 6 were unvaccinated with a history of the disease. Overall disease severity was mild, the authors note.

Dr. Gould, from the Centers for Disease Control and Prevention in Atlanta, and his team estimated vaccine effectiveness as 85.4% for one dose and 89.1% for two doses, not a significant difference. The vaccine was 100% effective against severe disease.

"It is possible," they contend, "that higher two-dose coverage at the school would have prevented the second outbreak from occurring, or that high coverage with two doses of varicella vaccine will reduce the number of outbreaks in the population."

Pediatr Infect Dis J 2009;28:678-681.

Saturday, September 12, 2009

Flu Drugs Little Use for Children, UK Study Says

From Reuters Health Information

LONDON (Reuters) Aug 10 - Children should not routinely be given influenza drugs such as Tamiflu since there is no clear evidence they prevent complications and potentially harmful side effects may outweigh any benefits, British researchers said on Monday.

"While morbidity and mortality in the current pandemic remain low, a more conservative strategy might be considered prudent, given the limited data, side effects such as vomiting, and the potential for developing resistant strains of influenza," they said.

Governments around the world have built up stockpiles of Roche's Tamiflu and GlaxoSmithKline's Relenza to deal with the current H1N1 swine flu pandemic.

In Britain, hundreds of thousands of doses of Tamiflu have been handed out to people with the disease, of whom around half are children.

But Matthew Thompson from the University of Oxford and colleagues reported in the British Medical Journal that while antivirals shortened the duration of flu in children by around a day, they didn't reduce asthma flare-ups or the likelihood of children needing antibiotics.

Tamiflu was also linked to an increased risk of vomiting, which can be serious in children.

The analysis was based on a systematic review of seven previous clinical studies looking at use of Tamiflu and Relenza in seasonal flu outbreaks in children aged 1 to 12 years.

Thompson told reporters there was no reason to think the conclusions would not also apply to the current relatively mild outbreak of swine flu.

SOURCE: BMJ, online first August 10, 2009.

Friday, September 11, 2009

HPV Vaccines: Cervarix Approval and Gardasil Use in Boys/Men Recommended by FDA Advisory Committee

From Medscape Medical News
Zosia Chustecka

September 11, 2009 — A second vaccine against human papillomavirus (HPV) for the prevention of cervical cancer — GlaxoSmithKline's Cervarix — has been recommended for approval in the United States; the extended use of Merck & Co's Gardasil, the first vaccine, was recommended for boys and men for the prevention of genital warts.

The recommendations came from the US Food and Drug Administration (FDA) Vaccines and Related Biological Products Advisory Committee. In both cases, the voting was almost unanimously in favor, with only 1 abstention or no vote, but the meeting heard concerns about the safety of the vaccines and questions about the public-health value of the extended indication.

The voting on Cervarix was carried out by 13 members of the committee. There were 12 votes in favor of and 1 vote against the data supporting its efficacy in preventing precancerous lesions and cervical cancer in females in the 15 to 25 year age group and, from immunobridging studies, the 10 to 14 year age group. One member left the meeting before the vote on safety, but 11 of the remaining members voted in favor of the data supporting the safety of Cervarix in this population; there was 1 vote against.

Eight members of the committee voted on Gardasil use in boys and men. The vote was 7 in favor of the efficacy data supporting the use of Gardasil in males 9 to 25 years of age for the indication of preventing genital warts; there was 1 abstention. The vote was also 7 in favor of the data supporting the safety of Gardasil in this population; there was 1 vote against.

The FDA usually — but not always — follows the recommendations of its advisory committees.

Second Vaccine for Cervical Cancer

If approved, Cervarix would be the second HPV vaccine available in the United States. It is already marketed in more than 100 countries worldwide, including the 27 member states of the European Union. This product has been used in nationwide vaccination programs in the United Kingdom and Australia since it was first approved in 2007. At the meeting, the manufacturer estimated that around 7 million doses have been distributed worldwide.

Ceravix is a bivalent vaccine, active against HPV types 16 and 18, which together are thought to be responsible for about 70% of all cervical cancer cases. However, data from clinical trials presented at the committee meeting suggested that the vaccine also offers protection against other virus types responsible for causing cervical cancer, including HPV types 31, 33, and 45, the next most common cancer-causing strains. In addition, the data presented showed a duration of immunity of 6.4 years.

In contrast, Gardasil is a quadrivalent vaccine with activity against 4 HPV types: HPV types 16 and 18, which cause cervical cancer, and HPV types 6 and 11, which cause genital warts. This extra activity means that this vaccine is also indicated for the prevention of genital warts in girls and women, and it has now been recommended for that same indication for boys and men. However, the current data on Gardasil in males extends only out 2 to 3 years, and in women extends only out 5 years.

Is Cervarix Better at Protecting Against Cervical Cancer?

The main purpose behind the development of these HPV vaccines was to prevent cervical cancer, and for this indication, Cervarix is the better of the 2 vaccines, said Diane Harper, MD, from the University of Missouri–Kansas City School of Medicine. She has been involved in clinical trials with both vaccines, and was approached by Medscape Oncology for comment.

Dr. Harper outlined the following reasons for her opinion:

Cervarix and Gardasil are equally effective for HPV types 16 and 18 in women with no previous HPV, but Cervarix has proven to have a longer duration than Gardasil (6.4 vs 5 years);
there are still no data on how long the protection will ultimately last, and whether booster shots will be needed.
Cervarix offers cross protection for 5 cervical-cancer-causing types of HPV, whereas Gardasil offers cross protection for 3. In addition, Cervarix offers protection against the 3 most common types of HPV that cause adenocarcinoma, which is very difficult to detect with Pap testing; Gardasil is deficient in 1 of those types.
Cervarix prevents nearly twice the number of excisional therapies as does Gardasil (70% vs 40%), which is one of the harms that Pap screening can cause (excisional therapies lead to reproductive morbidity).

The antibody titers induced by Cervarix are superior to those for Gardasil, and are superior for women older than 25 years, should there come a time when the vaccines are approved for optional use by women in this age group. The antibody titers in the cervical mucous are also superior with Cervarix, and it is in the mucous on the epithelial surface that "half the action happens."
"I realize that this may sound like an advertisement for Cervarix, but these are the facts" Dr. Harper explained. "If you bother to vaccinate in countries with screening, then you want to vaccinate with the vaccine that will offer you the greatest cancer protection," she said.

Voting Against the Vaccines

The votes against both vaccines came from the consumer representative on the committee, Vicky Debold, PhD, RN, director of patient safety at the National Vaccine Information Center. She told Medscape Oncology that she has concerns about the safety of these vaccines, and acknowledged that her view is colored by listening to reports of adverse events from members of the public, in particular parents whose daughters who have suffered after vaccination with Gardasil.

"I'm not quite sure what is going on, but there have been too many patients with problems," she said. "There have been reports of demyelinating conditions and also deaths, and I wonder if there is a tendency toward a hyperstimulating of the immune system that results in such catastrophic outcomes." She suspects that there are individuals who might be particularly susceptible to adverse effects, maybe because of pre-existing conditions or genetic vulnerability.

It is very difficult to assess the safety of vaccines, Dr. Debold noted. At the meeting, she pointed out that, in many cases, the trials of both vaccines did not use a true placebo, such as a saline injection. The trials of Gardasil used an adjuvant control, and some of the Cervarix studies used hepatitis A vaccine as the control. "This makes the data very confusing," she said.

In addition, Dr. Debold had an issue with the way the question on the efficacy of Cervarix was worded. She felt the data showed that the vaccine did prevent precancerous lesions (and she would have voted yes for that), but the question also included wording about the prevention of cervical cancer, "and the data do not show this, not yet. The implication is that by preventing the earlier lesions, you prevent cervical cancer, but that is an implication, it has not been shown," she said.

At the meeting, specific questions about the safety of Cervarix focused on an "imbalance" of reports of spontaneous abortions and autoimmune adverse effects, but experts at the meeting were not convinced that these reports were related to the vaccine, with 1 commenting that "there are quirks in the collection of data."

Other Benefits From the Vaccines

Another potential benefit from a vaccine such as Gardasil that is active against HPV types 6 and 11 is that it might also offer protection against other "warty" diseases, including juvenile respiratory papillomatosis. Speaking during the open part of the meeting, Craig Derkay, MD, pediatric otolaryngologistat the Eastern Virginia Medical School in Norfolk, noted that there are about 1500 new cases each year of laryngeal papilloma caused by HPV 6 and 11, with the infection usually acquired from the mother during passage through the birth canal. There are no adjuvant therapies for this disease, and surgery is often not curative, he said. A vaccine that targets HPV 6 and 11 could "substantially reduce" this disease burden, and might also prevent HPV-associated head and neck cancer. If an HPV vaccine is to be used, it is preferable to use one with the broader spectrum so as to also prevent these types of diseases, he said.

Also speaking in the open part of the meeting was Dianne Zuckerman, PhD, president of the National Research Center for Women and Families. She expressed concern about the lack of long-term efficacy data for Gardasil in boys and men. The trial data that were presented were for 2 years, but some of the seroconversion data were for only 7 months, she pointed out.

The boys of America are not facing an epidemic of genital warts.
The whole point of vaccinating boys 9 to 11 years old is to protect them from genital warts once they become sexually active, but some of the data showed that the antibody titers dropped off during the 2 years of the trial, which raises the concern that any protection offered by the vaccine could have worn off by the time these boys become sexually active. "The boys of America are not facing an epidemic of genital warts and we have time to wait for efficacy data," she said.

In addition, she pointed out that genital warts are not life-threatening, and the male genital cancers that the vaccine offers protection against, such as penile and anal cancer, are very rare in heterosexual men.

One of the committee members highlighted the natural history of genital warts, which he felt was important for the discussion. "While they are ugly and a nuisance, they are also self-limiting and will go away on their own in individuals with a normal immune system," he said.

Approached for comment, Maurie Markman, MD, professor of gynecologic medical oncology at the University of Texas MD Anderson Cancer Center in Houston, who is an editorial advisor for Medscape Oncology, said: "I suspect evidence supporting the protection of males from genital warts will need to be very strong for the FDA to approve [this indication]. There is a very strong theoretical rationale to support vaccination of males to prevent cervix cancer in women, but considering the current cost of vaccination, I would seriously question the cost-effectiveness of this approach, at least in the United States. Further, there may be genuine protection of males against the risk of head and neck and other uncommon cancers, but again, this will need to be demonstrated in the clinical-trials setting."

Also during the open part of the meeting, there were testimonials from 2 mothers whose daughters had suffered adverse effects after vaccination with Gardasil, one of whom died shortly after her third dose. One of these mothers suggested that there was a link between niacin deficiency and adverse reactions to the HPV vaccine, and that individuals with pyruvate kinase deficiency might be particularly susceptible.

Paradigm-Shifting Prevention Strategy

Speaking out in favor of HPV vaccination — indeed, describing it as a "paradigm-shifting prevention strategy for cervical cancer" — was Mark Einstein, MD, MS, director of clinical research for women's health and gynecologic oncology at the Albert Einstein College of Medicine, in the Bronx, New York; he was representing the Society of Gynecologic Oncologists.

Cervical cancer remains a clinically relevant problem with in the United States, he told the meeting, with 11,000 new cases diagnosed annually, and about half a million women affected annually by precancerous lesions that could affect their reproductive health.

"The public-health value of the protection afforded by HPV vaccination overwhelmingly outweighs the self-limiting local side effects and even the rare but more serious effects that may or may not be vaccine-related," he told the meeting.

Zosia Chustecka is news editor for Medscape Hematology-Oncology and prior news editor of, a Web site acquired by WebMD. A veteran medical journalist based in London, UK, she has won a prize from the British Medical Journalists Association and is a pharmacology graduate. She has written for a wide variety of publications aimed at the medical and related health professions. She can be contacted at

Thursday, September 10, 2009

Delayed BCG Vaccine May Improve Immune Response Against TB

From Reuters Health Information
By C. Vidya Shankar

NEW YORK (Reuters Health) Sep 04 - BCG vaccine administered at 10 weeks of age produces a better immune response against Mycobacterium tuberculosis than when given at birth, according to the results of a small study from South Africa, published in the September issue of Vaccine.

The protective effect of BCG against tuberculosis varies depending on such issues as the vaccine strain, the route of administration, dose and host immune response, Dr. Willem Hanekom and colleagues explain. As the cell-mediated immune response is "immature" at birth, delaying the vaccine could enhance the immune response, they propose.

To test their hypothesis, Dr. Hanekom, from the University of Capetown, and his team conducted a randomized trial in which 25 neonates received BCG vaccine by intradermal injection at birth, whereas 21 received it at ten weeks of age. Infants in both groups were born healthy at term to HIV-negative mothers, and had no contact with tuberculosis.

The immune response to BCG was assessed 10 weeks and 1 year after vaccination by assay of the cytokines interferon gamma, tumor necrosis factor-alpha, and Interleukin-2, all produced by T helper 1 CD4 T cells.

Cytokine production by BCG-specific CD4 T cells were significantly greater among the delayed vaccine group both at 10 weeks and 1 year after vaccination, they observed. The response was most significant one year after vaccination, they note.

"Delayed vaccination resulted in an enhanced memory CD4 T cell response at 1 year of age," Dr. Hanekom observed. This results in improved long-term immunity, "particularly of the kind regarded as important for protection against TB," he explained.

The researcher noted that delayed BCG vaccine resulted in an increased production of "polyfunctional" BCG-specific CD4 T cells. "Polyfunctional cells make multiple cytokines together -- we think these cells are important for protection against TB," he said.

If these findings are confirmed by larger studies, they "could have wide-ranging implications for BCG vaccination practices, world-wide," Dr. Hanekom concluded.

Vaccine 2009;27:5488-5495.

Fits & Fever

From Medscape Medical News
Antipyretic Agents May Not Prevent Febrile Seizures
Laurie Barclay, MD

September 9, 2009 — Antipyretic agents may not prevent febrile seizures, according to the results of a randomized, placebo-controlled, double-blind trial reported in the September issue of the Archives of Pediatrics & Adolescent Medicine.

"The general assumption has been that fever is the key factor in the initiation of a febrile seizure, and it has, therefore, been supposed that the administration of antipyretic agents during febrile episodes will prevent seizures and their recurrences by the lowering of the fever," write Teemu Strengell, MD, from the University of Oulu in Oulu, Finland, and colleagues.

"This has not proved to be the case in clinical trials, however."
The goal of this study was to assess the effectiveness of different antipyretic agents and their highest recommended doses for preventing febrile seizures. At 5 hospitals, each of which was the only pediatric hospital in its region, 231 children who had their first febrile seizure between January 1, 1997, and December 31, 2003, were enrolled and observed for 2 years.

During follow-up, all febrile episodes were treated first with either rectal diclofenac or placebo, and after 8 hours, treatment was continued with oral ibuprofen, acetaminophen, or placebo. The primary endpoint of the study was recurrence of febrile seizures.

Of 851 febrile episodes occurring during follow-up, 89 were associated with a febrile seizure. Of the 231 children enrolled, 54 (23.4%) had recurrent febrile seizures. The treatment groups did not differ significantly in the main measure of effect, and the effect estimates were similar. The rate of febrile seizure recurrence was 23.4% (46/197) in those receiving antipyretic agents and 23.5% (8/34) in those receiving placebo (difference, 0.2; 95% confidence interval [CI], −12.8 to 17.6; P = .99).

Independent of the medication given, fever was significantly higher during the episodes with seizure vs those without seizure (39.7°C vs 38.9°C; difference, 0.7°C; 95% CI, −0.9°C to −0.6°C; P < .001).

"Antipyretic agents are ineffective for the prevention of recurrences of febrile seizures and for the lowering of body temperature in patients with a febrile episode that leads to a recurrent febrile seizure," the study authors write.

Limitations of this study include inability to exclude the possibility of a lesser effect that could be detected with a greater sample size. Parents were permitted to give their child an extra dose of open-label acetaminophen for temperature greater than 40.0°C, which could cause some dilutional bias.

"Because antipyretic agents are effective during a febrile episode that does not lead to a seizure, their use should not differ between patients with and without previous febrile seizures," the study authors conclude. "Parents should be informed about the inefficacy of antipyretic agents during a febrile episode that leads to a febrile seizure and about the benign nature of febrile seizures themselves."

Special State Grants for Health Research in the Department of Pediatrics and Adolescence in the Oulu University Hospital supported this study. The study authors have disclosed no relevant financial relationships.

Arch Pediatr Adolesc Med. 2009;163:799-804.

Wednesday, September 9, 2009

Eggs & Cholesterol?

Current Recommendations

The American Heart Association[31,32] Diet and Lifestyle Recommendations for Cardiovascular Disease Risk Reduction are listed in Table 1. The current recommendations reflect a shift toward looking at dietary patterns and overall diet quality rather than focusing on specific nutrients and a diet based more on inclusion of a wide range of foods and less on avoidance of particular foods or ingredients. Whereas there was previously a stated recommendation to limit eggs to 4 yolks per week, this food-specific recommendation is not in the current guidelines. The American Heart Association recommendation is to limit dietary cholesterol to <300 mg/d. The average egg yolk contains on average 213 mg of cholesterol.

If eggs are judged on their nutritional content, convenience, and cost, the positive contributions of eggs may outweigh the potential risk associated with the cholesterol. This may be particularly true for healthy elderly individuals whose cholesterol risk and nutritional needs differ from earlier years. For individuals with diabetes or major risk factors for CHD, the recommendation to limit dietary cholesterol to <200 mg/d[33] allows for less frequent use of unmodified egg products. Along with the numerous modified egg products on the market today (eg, Egg Beaters), there will likely be additional egg and egg products with higher lutein and lower cholesterol in the future.[34,35]

Table 1. American Heart Association 2006 Diet and Lifestyle Recommendations for Cardiovascular Disease Risk Reduction[32]
Balance calorie intake and physical activity to achieve or maintain a healthy body weight
Consume a diet rich in vegetables and fruit
Choose whole-grain, high-fiber foods
Consume fish, especially fatty fish, at least twice per week
Limit your intake of saturated fat to <7% of energy, trans fat to <1% of energy, and cholesterol to <300 mg/d by
Choosing lean meats and vegetable alternatives
Selecting fat-free (skim), 1% fat, and low-fat dairy products
Minimizing the intake of partially hydrogenated fats
Minimize the intake of beverages and foods with added sugars
Choose and prepare foods with little or no salt
If you consume alcohol, do so in moderation
When you eat food prepared outside of the home, follow American Heart Association diet and lifestyle recommendations

for whole article see blog

Saturday, September 5, 2009

Report New Cases of Guillain-Barré After H1N1 Flu Vaccine

From Medscape Medical News
Allison Gandey

September 1, 2009 — Neurologists should be vigilant in tracking any new cases of Guillain-Barré syndrome after patients have received the H1N1 flu vaccine, say officials. The American Academy of Neurology (AAN) is teaming up with the Centers for Disease Control and Prevention (CDC) to make sure doctors remain alert.

Guillain-Barré has been linked to several vaccines, including the preparation for the 1976 swine flu. In a statement issued by the AAN, experts said that although they do not expect the 2009 H1N1 vaccine to increase the risk for the autoimmune disease, this is a concern with any pandemic vaccine. "The active participation of neurologists is going to be critical for monitoring for any possible increase in Guillain-Barré following 2009 H1N1 influenza vaccination," AAN spokesperson Orly Avitzur, MD, said in a news release.

The H1N1 vaccine is currently in production. High-risk groups will be encouraged to receive the vaccine this fall. Infants, children, young adults, pregnant women, adults 25 years and older with underlying health conditions, and healthcare workers are considered good candidates for the vaccine.

Doctors are being asked to report adverse events using the standard CDC and US Food and Drug Administration Vaccine Adverse Event Reporting System.

Guillain-Barré affects 1 to 4 people per 100,000 annually around the world. It causes respiratory failure requiring ventilation in an estimated 25% of people, and between 4% and 15% die.

The AAN guidelines on the treatment of Guillain-Barré are available online.

Friday, September 4, 2009

First H1N1 Flu Vaccine Trials Underway

From Medscape Medical News
Emma Hitt

August 21, 2009 — No safety concerns have been reported with the H1N1 influenza vaccine so far in a clinical trial of adults and the elderly, and the planned trials are accruing well.

Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, spoke today at a US Centers for Disease Control and Prevention media briefing.

Five major trials are underway to evaluate H1N1 vaccines made by 2 manufacturers, Sanofi Pasteur and CSL Biotherapies. Two trials will compare 15 vs 30 μg and 1 vs 2 doses of each of the vaccines in healthy adults aged 18 years and older.

A comparable study is now underway in children aged 6 months to 17 years. A fourth and fifth trial will evaluate simultaneous vs sequential administration of the seasonal flu vaccine and the Sanofi Pasteur H1N1 vaccine in healthy adults and children, respectively.

First-dose data from the trial in adults are expected in mid-September, Dr. Fauci said. "If all goes well, second-dose data will be available somewhere around mid-October," he added. According to Dr. Fauci, the apparent safety of the vaccine in the trial of adults triggered the initiation of the pediatric trial on August 19 and 20.

Trials scheduled to begin in early September will evaluate 3 vaccine products in pregnant women, using 1 vs 2 doses and 15 vs 30 μg, with approximately 120 pregnant women in each trial.

Trials are also being planned for the use of adjuvants in "what we call a mix and match, where we take the antigen from one company and use the adjuvant from another company," Dr. Fauci said. "Those studies are scheduled to start somewhere in mid- to late September." Overall, about 4500 individuals will be studied in the clinical trials of the vaccines.

Jay Butler, MD, director, H1N1 Vaccine Task Force, Centers for Disease Control and Prevention, provided an update of US H1N1 statistics, as well as a report on activity in the Southern hemisphere and the status of vaccine production.

To date, there have been 7963 hospitalizations and 522 deaths that have been laboratory confirmed as being caused by novel H1N1 virus. "It's important to keep in mind that these numbers radically underestimate the number of cases that actually occur," he noted.

Seasonal flu activity has all but stopped, and nearly all cases now observed are H1N1. "Two states, Alaska and Maine, are reporting widespread influenza activity at this time," he said.

According to Dr. Butler, activity in the Southern hemisphere appears to be decreasing. In addition, the epidemiology of the disease caused by the virus in the Southern hemisphere is "very similar to that described in the United States this past spring," he said.

"There have been no significant changes detected in the influenza virus isolated from persons in the southern hemisphere as compared to viruses isolated from persons in the northern hemisphere," said Dr. Butler.

Five manufacturers are contracted to make the vaccine. Availability of between 45 million and 52 million doses of vaccine is expected by mid-October, and "this will be followed by weekly availability of vaccine up to about 195 million doses by the end of the year." However, Dr. Butler pointed out that many unforeseen variables can influence the production process.

Disclosure: Emma Hitt, PhD, has disclosed no relevant financial relationships.

Thursday, September 3, 2009

FDA Safety Labeling Changes : Gardasil

From Medscape Medical News >
FDA Safety Changes: Actonel, Gardasil, Myfortic

Yael Waknine

September 2, 2009 — The US Food and Drug Administration (FDA) has approved safety labeling revisions to warn of the potential for osteonecrosis of the jaw in patients receiving risedronate sodium and other bisphosphonates, the potential for syncope after administration of a human papillomavirus vaccine, and the risk for pure red cell aplasia in patients receiving immunosuppressive treatment with mycophenolic acid delayed-release tablets.

HPV Vaccine (Gardasil) May Be Linked to Postinjection Fainting Episodes

The FDA approved in July safety labeling revisions for human papillomavirus (HPV) quadrivalent recombinant vaccine (Gardasil; Merck and Co, Inc) to warn of the potential for syncope.

Syncope, sometimes associated with tonic-clonic and other seizure-like activity, has been reported after administration of the HPV vaccine. Because fainting can result in falling and injury, patients should be observed for a 15-minute period after receiving the vaccine and encouraged to remain seated or lying down for this length of time.

The FDA notes that when syncope is associated with tonic-clonic movements, the activity is usually transient and typically passes when patients adopt a supine or Trendelenburg position.

The quadrivalent vaccine is indicated for use in girls and young women aged 9 through 26 years for the prevention of cervical, vulvar, and vaginal cancer caused by HPV types 16 and 18; genital warts caused by HPV types 6 and 11; and certain dysplastic lesions caused by HPV types 6, 11, 16, and 18.

Gardasil Prescribing Information