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WHAT'S NEW THIS SUNDAY

Saturday, 4th of February 2012

 

• WHAT’S NEW THIS SUNDAY: GLOBAL MALARIA MORTALITY, NEW STUDIES OF BCG, HPV VACCINE SCARES
• GLOBAL MALARIA MORTALITY BETWEEN 1980 AND 2010,

Mortality trends are, in recent years, down, say the authors. WHO estimates are lowball, they also say, because of underestimates of mortality in those aged five and older.

'Global malaria deaths increased from 995 000 (95% uncertainty interval 711 000—1 412 000) in 1980 to a peak of 1 817 000 (1 430 000—2 366 000) in 2004, decreasing to 1 238 000 (929 000—1 685 000) in 2010.'

Full text at http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60034-8/fulltext ; see also editorial at http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60169-X/fulltext and Lancet podcast.

From the University of Washington. Always something new from Seattle.

The Lancet, Volume 379, Issue 9814, Pages 413 - 431, 4 February 2012

Global malaria mortality between 1980 and 2010: a systematic analysis

Original Text

Prof Christopher JL Murray MD a , Lisa C Rosenfeld AB a, Stephen S Lim PhD a, Kathryn G Andrews AB a, Kyle J Foreman MPH a, Diana Haring BSc a, Nancy Fullman MPH a, Mohsen Naghavi MD a, Prof Rafael Lozano MD a, Prof Alan D Lopez PhD b

Summary

Background

During the past decade, renewed global and national efforts to combat malaria have led to ambitious goals. We aimed to provide an accurate assessment of the levels and time trends in malaria mortality to aid assessment of progress towards these goals and the focusing of future efforts.

Methods

We systematically collected all available data for malaria mortality for the period 1980—2010, correcting for misclassification bias. We developed a range of predictive models, including ensemble models, to estimate malaria mortality with uncertainty by age, sex, country, and year. We used key predictors of malaria mortality such as Plasmodium falciparum parasite prevalence, first-line antimalarial drug resistance, and vector control. We used out-of-sample predictive validity to select the final model.

Findings

Global malaria deaths increased from 995 000 (95% uncertainty interval 711 000—1 412 000) in 1980 to a peak of 1 817 000 (1 430 000—2 366 000) in 2004, decreasing to 1 238 000 (929 000—1 685 000) in 2010. In Africa, malaria deaths increased from 493 000 (290 000—747 000) in 1980 to 1 613 000 (1 243 000—2 145 000) in 2004, decreasing by about 30% to 1 133 000 (848 000—1 591 000) in 2010. Outside of Africa, malaria deaths have steadily decreased from 502 000 (322 000—833 000) in 1980 to 104 000 (45 000—191 000) in 2010. We estimated more deaths in individuals aged 5 years or older than has been estimated in previous studies: 435 000 (307 000—658 000) deaths in Africa and 89 000 (33 000—177 000) deaths outside of Africa in 2010.

Interpretation

Our findings show that the malaria mortality burden is larger than previously estimated, especially in adults. There has been a rapid decrease in malaria mortality in Africa because of the scaling up of control activities supported by international donors. Donor support, however, needs to be increased if malaria elimination and eradication and broader health and development goals are to be met.

Funding

The Bill & Melinda Gates Foundation.

• NEW STUDIES OF BCG: IMPLICATIONS FOR TUBERCULOSIS VACCINES

‘We now know that BCG is highly effective in mycobacteria-naive newborns, it can prevent M tuberculosis infection and disease,12 its efficacy may extend into adulthood,13 and that an inactivated whole-cell vaccine can boost BCG.14 The present demonstration that first immunisation with BCG is cost-effective despite only modest efficacy in children from a tuberculosis-endemic country will be useful in further expansion of BCG vaccine use, but it is also a reminder that improved vaccines against tuberculosis are urgently needed for mycobacteria-experienced children and adults.’

 

The Lancet Infectious Diseases, Early Online Publication, 8 November 2011

New studies of BCG: implications for tuberculosis vaccines

Also at http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(11)70317-6/fulltext

Original Text

C Fordham von Reyn a

BCG has been given to over 3 billion people since the early part of the 20th century. Although the vaccine is effective, its use was implemented before clinical-trial design had reached its current sophistication, and before sensitive in-vitro techniques of assessing cellular immune responses were available. Recent studies and reinterpretation of previous trials have helped to clarify the true efficacy of BCG against both infection with and disease caused by Mycobacterium tuberculosis, while large cohort studies have provided an accurate side-effect profile in recipients with HIV infection. A contemporary understanding of BCG is crucial to the rational development of improved vaccines against tuberculosis.

The efficacy of immunisation with BCG depends largely on whether the vaccine recipient has pre-existing mycobacterial immunity on exposure to this live vaccine. Although overall efficacy in prospective trials has been estimated at 50%,1 striking differences exist between age groups on the basis of previous mycobacterial priming. A reanalysis of four prospective trials of BCG in mycobacteria-naive newborns (ie, no previous BCG, tuberculosis infection, or infection with non-tuberculous mycobacteria) indicated that immunisation was 73% effective against disease and 87% effective against death (in the period before availability of antibiotics).2 Although BCG side-effects (adenitis, disseminated disease) are an important issue for newborns, especially for those with HIV or congenital immunodeficiency, development of a more effective primary vaccine for infants will be challenging.

Possible explanations for low efficacy in trials in children beyond infancy and adults include differences in vaccine strain, latitude, and method of administration; however, the most plausible answer relates to the high rate of previous infection with M tuberculosis or non-tuberculous mycobacteria in older children and adults. Previous infection has two consequences that reduce observed efficacy: it limits the in-vivo replication of BCG that is required for protection,3 and both non-tuberculous mycobacteria infection and latent M tuberculosis infection by themselves confer partial immune protection against subsequent tuberculosis.4, 5

BCG trials beyond the neonatal period typically relied on skin testing with tuberculin or non-tuberculous mycobacterial proteins to exclude participants with pre-existing mycobacterial reactivity. However, in-vitro studies show that people with negative skin tests may have in-vitro cellular responses to mycobacteria or antibodies to common mycobacterial antigens. In a study of adults in Tanzania, 94% of adults with HIV infection had skin-test reactivity or in-vitro reactivity to mycobacterial antigens.6 And in countries where tuberculosis is not endemic, as many as 30—40% of adults had skin-test reactions to non-tuberculous mycobacteria,7 and antibodies to the common mycobacterial cell-wall antigen, lipoarabinomannin, were present in 96% of people aged 15—18 years.8 Thus, an optimum improved vaccine for mycobacteria-experienced older children and adults might require an approach that avoids the need for replication of a live mycobacterial strain.

In another example of the effect of pre-existing mycobacterial immunity, the BCG REVAC trial9 from Brazil has shown that BCG boosters are not effective in improving protection of children with pre-existing BCG scars. In The Lancet Infectious Diseases, Susan M Pereira and colleagues10 report data from a large substudy of the BCG REVAC trial of children aged 7—14 years from the same cohort who did not have a BCG scar and therefore received what was classed as first immunisation with BCG. The vaccine was 25% (95% CI 3—43) effective against subsequent tuberculosis during 9 years of follow-up in 20 622 children. Tuberculin tests were not done but reactivity rates were estimated to be about 30% in this population,9 and one would expect detectable mycobacterial sensitivity to be even higher with in-vitro tests of cellular and humoral response.

The net effect of including such a substantial number of mycobacteria-experienced children would be to lower the apparent efficacy of BCG. Nevertheless, BCG vaccination had sufficient efficacy for the investigators to conclude that first immunisation of school-age children who had not received BCG at birth would be cost-effective. This finding has implications for other potential uses of the vaccine including first immunisation of adult health-care workers from developed countries working in health-care or refugee settings in which tuberculosis is endemic.

For inexpensive vaccines such as BCG, cost-efficacy can be influenced substantially by the severity and cost of side-effects.11 The most serious complication is disseminated disease, which can be fatal in infants with unrecognised congenital immunodeficiency syndromes or neonatal HIV infection. These disorders would be rare in children aged 7—14 years, contributing to a low rate of serious complications and favourable cost-efficacy in Brazil.

This excellent study adds to our growing understanding of the efficacy of BCG, which is crucial to the rational design and selection of new vaccines. We now know that BCG is highly effective in mycobacteria-naive newborns, it can prevent M tuberculosis infection and disease,12 its efficacy may extend into adulthood,13 and that an inactivated whole-cell vaccine can boost BCG.14 The present demonstration that first immunisation with BCG is cost-effective despite only modest efficacy in children from a tuberculosis-endemic country will be useful in further expansion of BCG vaccine use, but it is also a reminder that improved vaccines against tuberculosis are urgently needed for mycobacteria-experienced children and adults.

I declare that I have no conflicts of interest. I thank Peter F Wright for helpful comments on the comment.

References

1 Colditz GA, Brewer TF, Berkey CS, et al. Efficacy of BCG vaccine in the prevention of tuberculosis: meta-analysis of the published literature. JAMA 1994; 271: 698-702. PubMed

2 von Reyn CF, Vuola J. New vaccines for the prevention of tuberculosis. Clin Infect Dis 2002; 35: 465-474. CrossRef | PubMed

3 Brandt L, Cunha JF, Olsen AW, et al. Failure of the Mycobacterium bovis BCG vaccine: some species of environmental mycobacteria block multiplication of BCG and induction of protective immunity to tuberculosis. Infect Immun 2002; 70: 672-678. CrossRef | PubMed

4 Fine PEM. Variation in protection by BCG: implications of and for heterologous immunity. Lancet 1995; 346: 1339-1345. Summary | CrossRef | PubMed

5 Flahiff EW. The occurrence of tuberculosis in persons who failed to react to tuberculin, and in persons with positive tuberculin reactions. Am Jour Hyg 1939; 30: 69-74. PubMed

6 Matee M, Lahey T, Vuola JM, et al. Baseline mycobacterial immune responses in HIV-infected adults primed with bacille Calmette-Guerin during childhood and entering a tuberculosis booster vaccine trial. J Infect Dis 2007; 195: 118-123. CrossRef | PubMed

7 von Reyn CF, Horsburgh CR, Olivier KN, et al. Skin test reactions to Mycobacterium tuberculosis purified protein derivative and Mycobacterium avium sensitin among health care workers and medical students in the United States. Int J Tuber Lung Dis 2001; 5: 1122-1128. PubMed

8 Fairchok MP, Rouse JH, Morris SL. Age-dependent humoral responses of children to mycobacterial antigens. Clin Diagn Lab Immunol 1995; 2: 443-447. PubMed

9 Rodrigues LC, Pereira SM, Cunha SS, et al. Effect of BCG revaccination on incidence of tuberculosis in school-aged children in Brazil: the BCG-REVAC cluster randomized trial. Lancet 2005; 366: 1290-1295. Summary | Full Text | PDF(103KB) | CrossRef | PubMed

10 Pereira SM, Barreto ML, Pilger D, et al. Effectiveness and cost-effectiveness of first BCG vaccination against tuberculosis in school-age children without previous tuberculin test (BCG-REVAC trial): a cluster-randomised trial. Lancet Infect Dis 201110.1016/S1473-3099(11)70285-7. published online Nov 8. PubMed

11 Hersh AL, Tala-Heikkilä M, Tala E, Tosteson ANA, von Reyn CF. A cost-effectiveness analysis of universal versus selective immunization with Mycobacterium bovis bacille Calmette-Guerin in Finland. Int J Tuberc Lung Dis 2002; 7: 22-29. PubMed

12 Lalvani A, Sridhar S. BCG vaccination: 90 years on and still so much to learn. Thorax 2010; 65: 1036-1038. CrossRef | PubMed

13 Aronson NE, Santosham M, Comstock GW, et al. Long-term efficacy of BCG vaccine in American Indians and Alaska natives: a 60-year follow-up study. JAMA 2004; 291: 2086-2091. CrossRef | PubMed

14 von Reyn CF, Mtei L, Arbeit RD, et al. Prevention of tuberculosis in Bacille Calmette-Guerin-primed, HIV-infected adults boosted with an inactivated whole-cell mycobacterial vaccine. AIDS 2010; 24: 675-685. CrossRef | PubMed

a Infectious Disease and International Health, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA

HPV, VACCINE SCARES, AND MICHELE BACHMANN

 

• HPV, VACCINE SCARES, AND MICHELE BACHMAN

 From The New York Times

Remark on HPV Vaccine Could Ripple for Years

By DENISE GRADY

Published: September 19, 2011

During a debate last week for Republican presidential candidates and in interviews after it, Representative Michele Bachmann called the vaccine to prevent cervical cancer “dangerous.” Medical experts fired back quickly. Her statements were false, they said, emphasizing that the vaccine is safe and can save lives. Mrs. Bachmann was soon on the defensive, acknowledging that she was not a doctor or a scientist.

But the harm to public health may have already been done. When politicians or celebrities raise alarms about vaccines, even false alarms, vaccination rates drop.

“These things always set you back about three years, which is exactly what we can’t afford,” said Dr. Rodney E. Willoughby, a professor of pediatrics at the Medical College of Wisconsin and a member of the committee on infectious diseases of the American Academy of Pediatrics. The academy favors use of the vaccine, as do other medical groups and the Centers for Disease Control and Prevention.

The vaccine, recommended by the medical groups for 11- and 12-year-olds, protects against the human papillomavirus, or HPV, a sexually transmitted infection that can cause cancer. Use of the vaccine was disturbingly low even before the Bachmann flap, health officials say. That is partly because of the recent climate of fear about vaccines in general, and partly because some parents feel that giving the vaccine somehow implies that they are accepting or even condoning the idea that their young daughters will soon start having sex.

Allegations that vaccines could cause autism have frightened some parents away from giving them to children. But the question has been studied repeatedly, and there is no evidence for such a link; the research that first promoted the idea was subsequently proved fraudulent.

Indeed, a report published last month by the Institute of Medicine, which advises the government, found that the HPV vaccine was safe.

It did find “strong and generally suggestive” — though not conclusive — evidence that the vaccine could cause severe allergic reactions. But such reactions have been rare.

Historically, Dr. Willoughby said, vaccine scares have caused vaccination rates to drop for three or four years, and have led to outbreaks of diseases that had previously been under control, like measles and whooping cough. Measles cases in the United States reached a 15-year high last spring, with more than 100 cases, most in people who had never been vaccinated.

Once the disease begins to reappear, parents become worried and start vaccinating again. With cervical cancer, Dr. Willoughby said, “unfortunately, the outbreak is silent and will take 20 years to manifest.”

This time, he said, there will be no symptoms to scare parents back into vaccinating their daughters until it is too late.

HPV infection is extremely common — the most common sexually transmitted infection in the United States. More than a quarter of girls and women ages 14 to 49 have been infected, with the highest rate, 44 percent, in those ages 20 to 24.

Millions of new infections occur each year, and researchers think that at least half of all adults have been infected at some point in their lives. The genital region is teeming with HPV, and any kind of intimate contact — not just intercourse — can transmit the virus. In most people, HPV is harmless: The immune system fights it off. But in some people, for unknown reasons, the viruses persist and can cause cancer.

Although the HPV vaccine was initially approved in 2006 to prevent cervical cancer, more recent data has shown that HPV also causes cancers of the penis, anus, vagina, vulva and parts of the throat. Many scientists think that the vaccine can prevent those diseases as well.

Last month, the Centers for Disease Control and Prevention published a report on vaccination rates in girls that was “a call to action” to do a better job with the HPV vaccine, according to Dr. Melinda Wharton, deputy director of the National Center for Immunization and Respiratory Diseases.

“We’re not meeting our goals,” Dr. Wharton said. “Girls are not getting an important preventive measure that they need.”

Nationwide, last year only 32 percent of teenage girls received all three shots needed to prevent HPV infection, the disease centers found. Rates of vaccination were much higher (at least 45 percent) in a few states — Massachusetts, Rhode Island, Washington and South Dakota. Those furthest below average (20 percent or less) included Idaho, Mississippi, Arkansas and Alabama.

The report was particularly troubling, Dr. Wharton said, because it showed use of the HPV vaccine lagging far behind that of two other vaccines that were licensed around the same time, one for meningitis and a combination shot against tetanus, diphtheria and whooping cough.

“This vaccine has been portrayed as ‘the sex vaccine,’ ” said Dr. Mary Anne Jackson, a professor of pediatrics at the University of Missouri-Kansas City and a member of the infectious disease committee of the American Academy of Pediatrics. “Talking about sexuality for pediatricians and other providers is often difficult.”

Dr. William Schaffner, an infectious diseases expert at Vanderbilt University, acknowledged that 11 or 12 is “a pretty tender age, and parents are having a hard time getting used to this concept.”

But like the measles vaccine and others, this one must be given before a person is exposed to the virus or it will not work.

“Here we’d like to get it completed before the young woman initiates her sex life,” Dr. Schaffner said. “Of course parents, particularly fathers, think that’s going to happen at around age 34.”

The average age of first intercourse in the United States is about 17 for both boys and girls, according to the Kinsey Institute. About 25 percent have had sex by age 15.

Even before Mrs. Bachmann’s comments, family doctors were negotiating with reluctant, confused parents. Dr. Schaffner said he knew a pediatrician who postponed the HPV shots until most patients turned 15 specifically to avoid parents’ objections at the younger age.

“He thinks he can pick out the early adventurers because he knows them so well,” Dr. Schaffner said. “Those, he vaccinates earlier. Personally, I’m dubious about the success of this strategy. He may be no better than the parents figuring out who is doing what when.”

Dr. Willoughby said he thought the HPV vaccine might be more acceptable to parents if it were recommended even earlier in life, at a less fraught time than the cusp of puberty. Then it could be given, as most vaccines are, without parents’ or doctors’ feeling a need to give the child a detailed explanation. And there would not be the unspoken implication that sex was imminent.

“There’s probably no reason why it should be 11 or 12, as opposed to 5 or 6 or even birth,” Dr. Willoughby said. “If it were being given in kindergarten, I don’t think would be an adherence problem.”

So far, there is no evidence that the vaccine wears off over time, but if that does occur, Dr. Willoughby said, booster shots could be given.

There are many strains of HPV, but two of them, known as Type 16 and Type 18, cause 70 percent of all cervical cancers. Other strains can cause genital warts.

One version of the vaccine, Gardasil, made by Merck, works against the two cancer-causing strains and two other strains that are the most common causes of genital warts. Gardasil was approved for use in boys in 2009 to prevent genital warts, but medical groups like the pediatrics academy have not recommended it; that could change within the next few months.

Another version, Cervarix, made by GlaxoSmithKline, protects against only the cancer-causing strains, and is approved only for girls and women.

In studies comparing women who were vaccinated with those who were not, the vaccines were 93 to 100 percent effective at preventing infection with HPV Type 16 and Type 18, according to Dr. Deborah Saslow, the director for breast and gynecological cancer at the American Cancer Society.

Some critics of the vaccine have said it is not needed in the United States, arguing that cervical cancer is no longer common here: Pap tests are finding precancerous growths early enough to remove them before they turn into cancer. There are about 12,000 cases of cervical cancer and 4,000 deaths a year in the United States. (In developing countries, infection rates are much higher, and the disease is a leading cause of death in women.)

But deaths are only a small part of the trouble caused by HPV. Several hundred thousand women a year in the United States need surgery for precancerous lesions caused by the virus, and many more are treated for other cervical abnormalities linked to the infection.

The vaccines could prevent many of those cases and spare women the surgery, which can be painful and nerve-racking, and may impair a woman’s ability to carry a pregnancy to full term, Dr. Saslow said.

By June 2011, more than 35 million doses of the two cervical cancer vaccines had been distributed in the United States, according to the Centers for Disease Control and Prevention. The most common side effect is a sore arm from the shot. Though fainting has been reported, Dr. Jackson said that teenagers were more likely than younger children to faint after any injection.

When pediatricians recommend the vaccine, many parents still hesitate. Michele Boettiger, the mother of three daughters in Missouri City, Tex., said she struggled with the decision about whether to vaccinate them against HPV. She worried about whether the vaccine was safe.

As a Roman Catholic who believes in abstinence until marriage, she also wondered whether the vaccine would somehow send the wrong message, and act as “a gateway for young women to think they have sexual freedom.”

Ms. Boettiger, a nursing student, found reassurance in the endorsement of the vaccine by the disease centers and other medical groups, and in its acceptance by the National Catholic Bioethics Center.

Her father and her husband, the girls’ father, both died of cancer. “Our family suffered a loss from cancer,” she said. “It is not a battle I want to fight anytime soon.”

She has had her two older daughters vaccinated, and will do the same for the youngest.