Pro Vaccine Research Paper

Whooping cough, measles, mumps. These are the diseases that preyed on our parents' and grandparents' generations and that we thought were fading from existence. In fact, all three diseases have seen a resurgence in the past decade. In 2017 Minnesota suffered a measles outbreak: in a Somali-American community with previously high vaccination rates, concerns about autism led parents to refuse the MMR vaccine against measles, mumps and rubella, and measles spread among the unvaccinated. In 2015 a large multistate measles outbreak started at a California amusement park, and many of those infected were unvaccinated children.

These troubling events show that the failure to vaccinate children endangers both the health of children themselves as well as others who would not be exposed to preventable illness if the community as a whole were better protected. Equally troubling, the number of deliberately unvaccinated children has grown large enough that it may be fueling more severe outbreaks. In a recent survey of more than 1,500 parents, one quarter held the mistaken belief that vaccines can cause autism in healthy children, and more than one in 10 had refused at least one recommended vaccine.

This sad state of affairs exists because parents have been persistently and insidiously misled by information in the press and on the Internet and because the health care system has not effectively communicated the counterarguments, which are powerful. Physicians and other health experts can no longer just assume that parents will readily agree to childhood inoculations and leave any discussion about the potential risks and benefits to the last minute. They need to be more proactive, provide better information and engage parents much earlier than is usually the case.

Peril of business as usual

Right now pediatricians typically bring up the need for vaccines during the well-baby checkup held about two months after birth. That visit has a jam-packed agenda. In the usual 20 minutes allotted for the appointment, the physician must learn the answers to many questions, of which the following are but a sample: How many times is the baby waking to feed at night? Is the child feeding well? Where do measurements of height, weight and head circumference fall on a standard growth chart? Do the parents know how and when to introduce solid food and how to safely lay the child down to sleep? Are various reflexes good? Can the sounds of a heart murmur be heard through the stethoscope? Are the hip joints fitting properly in their sockets, or are they dislocated?

Generally in the final seconds of the visit, assuming all has gone well up to this point, the doctor mentions the required schedule for six recommended inoculations: the first DTaP shot (for diphtheria, tetanus and pertussis, also known as whooping cough), the polio shot, a second hepatitis B shot (the first having been given in the first few days after birth), the pneumococcal conjugate shot (for bacterial pneumonia and meningitis), the Hib shot (for another type of meningitis) and finally the oral rotavirus vaccine (to prevent a severe diarrheal infection). This is the point in the visit at which more and more pediatricians report a disheartening turn of events: although most parents agree to the inoculations without hesitation, a growing number say they would like to delay or even refuse some or all of the vaccinations for their infants.

A proper conversation that respects the reluctant parents' concerns, answers their questions and reassures them that the inoculations are indeed necessary—that countless studies by hundreds of researchers over many decades have shown that vaccinations save millions of lives—will likely take at least another 20 minutes. Meanwhile, though, other families sit in the waiting room, itching for their own well-baby checkups to start.

Having this discussion at the two-month well-baby visit is too late. By then, parents may have read about any issues on the Web or chatted with other moms and dads in the park. Discussion with medical professionals should begin long before, usually during, or even prior to, the pregnancy.

Fears and facts

Although parents give many reasons for not wanting to vaccinate their children, we have noticed at least three recurring themes. Some do not believe their children are at risk for diseases such as polio, measles and tetanus, which are now rarely seen in the U.S. Others do not believe that certain vaccine-preventable diseases, such as chicken pox and measles, are particularly serious. And many worry about the safety of vaccines. The concerns may be about immediate, well-defined side effects such as fever or may take the form of anxiety that vaccines might harm the immune system or cause chronic diseases years later. Each of these concerns can be met with a careful review of the evidence.

Together we have conducted a series of studies to better quantify the risks of not vaccinating—information that speaks to the mistaken belief that today's children are unlikely to come down with whooping cough, measles or the like if they skip their inoculations. Our investigations looked at hundreds of thousands of children in Colorado and compared the risk of various vaccine-preventable diseases in children whose parents had refused or delayed vaccines with the risk in children whose parents had had them vaccinated. We found that unvaccinated children were roughly 23 times more likely to develop whooping cough, nine times more likely to be infected with chicken pox, and 6.5 times more likely to be hospitalized with pneumonia or pneumococcal disease than vaccinated children from the same communities.

Clearly, the parental decision to withhold vaccination places youngsters at greatly increased risk for potentially serious infectious diseases. These results also show the flaws in the “free rider” argument, which erroneously suggests that an unvaccinated child can avoid any real or perceived risks of inoculation because enough other children will have been vaccinated to protect the untreated child.

Depending on fate to soften the blow from an infection is also more dangerous than most people realize. One out of every 20 previously healthy children who get the measles will come down with pneumonia. One out of 1,000 will suffer an inflammation of the brain that can lead to convulsions and mental retardation, and one to two out of 1,000 will die. Similarly, chicken pox can lead to severe infections of the skin, swelling of the brain, and pneumonia. Even when no complications arise, chicken pox is painful and triggers high fevers and itchy rashes. Vaccinated children who develop chicken pox (no vaccine is perfectly effective all the time) usually suffer much milder symptoms.

Even when parents appreciate the peril of not vaccinating, they want to know that vaccines are safe. Because vaccines are given to huge numbers of people, including healthy infants, they are held to a much higher safety standard than medications used for people who are already sick. Nothing in medicine is 100 percent safe, however, and the absolute safety of vaccines cannot be proved. Safety can be inferred, though, by the relative absence of serious side effects in multiple studies.

Studying the safety of vaccines is a complicated, labor-intensive process. Fortunately, the U.S. has a sophisticated system, a federally funded program that does not receive any money from vaccine manufacturers. This system can both test specific hypotheses and perform general monitoring of the safety of newly licensed vaccines. As a new theory arises, it can be rigorously tested.

Perhaps the biggest boost to the antivaccine movement came in 1998, when, in a paper in the Lancet, Andrew J. Wakefield and 12 colleagues proposed that the measles vaccine could cause autism in susceptible children. In the years since, more than a dozen studies have convincingly shown that vaccines do not cause autism. In fact, it is rare in science that published scientific findings have been so thoroughly, and publicly, disproved. The Lancet retracted the Wakefield article in early 2010. Most of the co-authors no longer vouch for the study findings. And Wakefield himself was accused of falsifying the data and lost his medical license.

Despite the complete dismantling of Wakefield's vaccines-cause-autism hypothesis, public skepticism about vaccination has only increased as new speculative theories have been put forward. Maybe, some contend, vaccine preservatives cause long-term problems. Or maybe the growing number of vaccines all assaulting the immature immune system at once causes complications. Or perhaps trouble can arise from a toxic combination of vaccines with air pollution, chemical and metal contamination of the environment, and the increasing stress of modern life.

This cycle—debunked links followed by ever grander speculation—keeps repeating itself and is a clear indication that the scientific community is more reactive than proactive when engaging the public about vaccine safety.

So where does this leave the conversation between parents and health professionals? Several promising strategies may be emerging. We recently completed a multiyear randomized controlled trial. We found that an Internet-based intervention delivered during pregnancy and early childhood successfully improved the vaccine attitudes of parents who were already hesitant about vaccination. The intervention also improved vaccination rates. Another group of researchers has found that using a presumptive approach (“Here are the vaccines we'll be giving today”) rather than a participatory style (“What do you want to do about vaccines today?”) was associated with a higher parental intention to vaccinate. While these strategies need to be explored further, we know that parents also want a nonjudgmental face-to-face conversation with their child's doctor. And many will still want their infant's doctor to look them in the eye and say, “This is one of the best things you can do for your child's health.”

The key facts parents need to know, though, are that vaccines prevent potentially fatal diseases, that vaccines have a high degree of safety, and that their safety is constantly evaluated and reevaluated in a system operating independently from the pharmaceutical companies that make vaccines. Unless this message gets spread widely and well, too many doctors and parents are going to find themselves in emergency rooms and isolation wards, watching children suffer with the devastating effects of measles, whooping cough or some other readily preventable infectious disease.

Liang Zhao | Arjun Seth | Nani Wibowo | Chun Xia Zhao | Neena Mitter | Chengzhong Yu | Anton P.J. Middelberg

Nanotechnology increasingly plays a significant role in vaccine development. As vaccine development orientates toward less immunogenic "minimalist" compositions, formulations that boost antigen effectiveness are increasingly needed. The use of nanoparticles in vaccine formulations allows not only improved antigen stability and immunogenicity, but also targeted delivery and slow release. A number of nanoparticle vaccines varying in composition, size, shape, and surface properties have been approved for human use and the number of candidates is increasing. However, challenges remain due to a lack of fundamental understanding regarding the in vivo behavior of nanoparticles, which can operate as either a delivery system to enhance antigen processing and/or as an immunostimulant adjuvant to activate or enhance immunity. This review provides a broad overview of recent advances in prophylactic nanovaccinology. Types of nanoparticles used are outlined and their interaction with immune cells and the biosystem are discussed. Increased knowledge and fundamental understanding of nanoparticle mechanism of action in both immunostimulatory and delivery modes, and better understanding of in vivo biodistribution and fate, are urgently required, and will accelerate the rational design of nanoparticle-containing vaccines. © 2013 The Authors.

Heidi J. Larson | Caitlin Jarrett | Elisabeth Eckersberger | David M.D. Smith | Pauline Paterson

Vaccine "hesitancy" is an emerging term in the literature and discourse on vaccine decision-making and determinants of vaccine acceptance. It recognizes a continuum between the domains of vaccine acceptance and vaccine refusal and de-polarizes previous characterization of individuals and groups as either anti-vaccine or pro-vaccine.The primary aims of this systematic review are to: 1) identify research on vaccine hesitancy; 2) identify determinants of vaccine hesitancy in different settings including its context-specific causes, its expression and its impact; and 3) inform the development of a model for assessing determinants of vaccine hesitancy in different settings as proposed by the Strategic Advisory Group of Experts Working Group (SAGE WG) for dealing with vaccine hesitancy.A broad search strategy, built to capture multiple dimensions of public trust, confidence and hesitancy around vaccines, was applied across multiple databases. Peer-reviewed studies were selected for inclusion if they focused on childhood vaccines [≤7 years of age], used multivariate analyses, and were published between January 2007 and November 2012.Our results show a variety of factors as being associated with vaccine hesitancy but they do not allow for a complete classification and confirmation of their independent and relative strength of influence. Determinants of vaccine hesitancy are complex and context-specific-varying across time, place and vaccines. © 2014 Elsevier Ltd.

Michael L. Jackson | Jennifer C. Nelson

Objective: The test-negative design has emerged in recent years as the preferred method for estimating influenza vaccine effectiveness (VE) in observational studies. However, the methodologic basis of this design has not been formally developed. Methods: In this paper we develop the rationale and underlying assumptions of the test-negative study. Under the test-negative design for influenza VE, study subjects are all persons who seek care for an acute respiratory illness (ARI). All subjects are tested for influenza infection. Influenza VE is estimated from the ratio of the odds of vaccination among subjects testing positive for influenza to the odds of vaccination among subjects testing negative. Results: With the assumptions that (a) the distribution of non-influenza causes of ARI does not vary by influenza vaccination status, and (b) VE does not vary by health care-seeking behavior, the VE estimate from the sample can generalized to the full source population that gave rise to the study sample. Based on our derivation of this design, we show that test-negative studies of influenza VE can produce biased VE estimates if they include persons seeking care for ARI when influenza is not circulating or do not adjust for calendar time. Conclusions: The test-negative design is less susceptible to bias due to misclassification of infection and to confounding by health care-seeking behavior, relative to traditional case-control or cohort studies. The cost of the test-negative design is the additional, difficult-to-test assumptions that incidence of non-influenza respiratory infections is similar between vaccinated and unvaccinated groups within any stratum of care-seeking behavior, and that influenza VE does not vary across care-seeking strata. © 2013 Elsevier Ltd.

Ivo M. Foppa | Michael Haber | Jill M. Ferdinands | David K. Shay

Background: A modification to the case-control study design has become popular to assess vaccine effectiveness (VE) against viral infections. Subjects with symptomatic illness seeking medical care are tested by a highly specific polymerase chain reaction (PCR) assay for the detection of the infection of interest. Cases are subjects testing positive for the virus; those testing negative represent the comparison group. Influenza and rotavirus VE studies using this design are often termed "test-negative case-control" studies, but this design has not been formally described or evaluated. We explicitly state several assumptions of the design and examine the conditions under which VE estimates derived with it are valid and unbiased. Methods: We derived mathematical expressions for VE estimators obtained using this design and examined their statistical properties. We used simulation methods to test the validity of the estimators and illustrate their performance using an influenza VE study as an example. Results: Because the marginal ratio of cases to non-cases is unknown during enrollment, this design is not a traditional case-control study; we suggest the name "case test-negative" design. Under sets of increasingly general assumptions, we found that the case test-negative design can provide unbiased VE estimates. However, differences in health care-seeking behavior among cases and non-cases by vaccine status, strong viral interference, or modification of the probability of symptomatic illness by vaccine status can bias VE estimates. Conclusions: Vaccine effectiveness estimates derived from case test-negative studies are valid and unbiased under a wide range of assumptions. However, if vaccinated cases are less severely ill and seek care less frequently than unvaccinated cases, then an appropriate adjustment for illness severity is required to avoid bias in effectiveness estimates. Viral interference will lead to a non-trivial bias in the vaccine effectiveness estimate from case test-negative studies only when incidence of influenza is extremely high and duration of transient non-specific immunity is long. © 2013 Elsevier Ltd.

Leonoor Wijnans | Coralie Lecomte | Corinne de Vries | Daniel Weibel | Cormac Sammon | Anders Hviid | Henrik Svanström | Ditte Mølgaard-Nielsen | Harald Heijbel | Lisen Arnheim Dahlström | Jonas Hallgren | Par Sparen | Poul Jennum | Mees Mosseveld | Martijn Schuemie | Nicoline van der Maas | Markku Partinen | Silvana Romio | Francesco Trotta | Carmela Santuccio | Angelo Menna | Giuseppe Plazzi | Keivan Kaveh Moghadam | Salvatore Ferro | Gert Jan Lammers | Sebastiaan Overeem | Kari Johansen | Piotr Kramarz | Jan Bonhoeffer | Miriam C.J.M. Sturkenboom

Background: In August 2010 reports of a possible association between exposure to AS03 adjuvanted pandemic A(H1N1)pdm09 vaccine and occurrence of narcolepsy in children and adolescents emerged in Sweden and Finland. In response to this signal, the background rates of narcolepsy in Europe were assessed to rapidly provide information for signal verification. Methods: We used a dynamic retrospective cohort study to assess the narcolepsy diagnosis rates during the period 2000-2010 using large linked automated health care databases in six countries: Denmark, Finland, Italy, the Netherlands, Sweden and the United Kingdom. Results: Overall, 2608 narcolepsy cases were identified in almost 280 million person years (PY) of follow up. The pooled incidence rate was 0.93 (95% CI: 0. 90-0.97) per 100,000 PY. There were peaks between 15 and 30 year of age (women > men) and around 60 years of age. In the age group 5-19 years olds rates were increased after the start of pandemic vaccination compared to the period before the start of campaigns, with rate ratios (RR) of 1.9 (95% CI: 1.1-3.1) in Denmark, 6.4 (95% CI: 4.2-9.7) in Finland and 7.5 (95% CI: 5.2-10.7) in Sweden. Cases verification in the Netherlands had a significant effect on the pattern of incidence over time. Conclusions: The results of this incidence study provided useful information for signal verification on a population level. The safety signal of increased narcolepsy diagnoses following the start of the pandemic vaccination campaign as observed in Sweden and Finland could be observed with this approach. An increase in narcolepsy diagnoses was not observed in other countries, where vaccination coverage was low in the affected age group, or did not follow influenza A(H1N1)pdm09 vaccination. Patient level analyses in these countries are being conducted to verify the signal in more detail. © 2012 Elsevier Ltd.

Luke E. Taylor | Amy L. Swerdfeger | Guy D. Eslick

There has been enormous debate regarding the possibility of a link between childhood vaccinations and the subsequent development of autism. This has in recent times become a major public health issue with vaccine preventable diseases increasing in the community due to the fear of a 'link' between vaccinations and autism. We performed a meta-analysis to summarise available evidence from case-control and cohort studies on this topic (MEDLINE, PubMed, EMBASE, Google Scholar up to April, 2014). Eligible studies assessed the relationship between vaccine administration and the subsequent development of autism or autism spectrum disorders (ASD). Two reviewers extracted data on study characteristics, methods, and outcomes. Disagreement was resolved by consensus with another author. Five cohort studies involving 1,256,407 children, and five case-control studies involving 9,920 children were included in this analysis. The cohort data revealed no relationship between vaccination and autism (OR: 0.99; 95% CI: 0.92 to 1.06) or ASD (OR: 0.91; 95% CI: 0.68 to 1.20), nor was there a relationship between autism and MMR (OR: 0.84; 95% CI: 0.70 to 1.01), or thimerosal (OR: 1.00; 95% CI: 0.77 to 1.31), or mercury (Hg) (OR: 1.00; 95% CI: 0.93 to 1.07). Similarly the case-control data found no evidence for increased risk of developing autism or ASD following MMR, Hg, or thimerosal exposure when grouped by condition (OR: 0.90, 95% CI: 0.83 to 0.98; p= 0.02) or grouped by exposure type (OR: 0.85, 95% CI: 0.76 to 0.95; p= 0.01). Findings of this meta-analysis suggest that vaccinations are not associated with the development of autism or autism spectrum disorder. Furthermore, the components of the vaccines (thimerosal or mercury) or multiple vaccines (MMR) are not associated with the development of autism or autism spectrum disorder. © 2014 Elsevier Ltd.

Lisa A. Jackson | Alejandra Gurtman | Martin van Cleeff | Kathrin U. Jansen | Deepthi Jayawardene | Carmel Devlin | Daniel A. Scott | Emilio A. Emini | William C. Gruber | Beate Schmoele-Thoma

Background: Streptococcus pneumoniae is a major cause of morbidity and mortality among adults 50 years of age and older in the United States. Pneumococcal conjugate vaccines are efficacious against pneumococcal disease in children and may also offer advantages in adults. Methods: We performed a randomized, modified double-blind trial that compared a single dose of 13-valent pneumococcal conjugate vaccine (PCV13) with 23-valent pneumococcal polysaccharide vaccine (PPSV23) in 831 pneumococcal vaccine naive adults 60-64 years of age. An additional group of 403 adults 50-59 years of age received open-label PCV13. Anti-pneumococcal opsonophagocytic activity (OPA) titers were measured at baseline, and at 1 month and 1 year after vaccination. Results: In the randomized trial, the month 1 post-vaccination OPA geometric mean titers in the PCV13 group were statistically significantly higher than in the PPSV23 group for 8 of the 12 serotypes common to both vaccines and for serotype 6A, a serotype unique to PCV13, and were comparable for the other 4 common serotypes. The immune response to PCV13 was generally greater in adults 50-59 years of age compared to adults 60-64 years of age. OPA titers declined from 1 month to 1 year after PCV13 administration but remained higher than pre-vaccination baseline titers. Conclusions: PCV13 induces a greater functional immune response than PPSV23 for the majority of serotypes covered by PCV13, suggesting that PCV13 could offer immunological advantages over PPSV23 for prevention of vaccine-type pneumococcal infection. © 2013 The Authors.

Catherine Satzke | Paul Turner | Anni Virolainen-Julkunen | Peter V. Adrian | Martin Antonio | Kim M. Hare | Ana Maria Henao-Restrepo | Amanda J. Leach | Keith P. Klugman | Barbara D. Porter | Raquel Sá-Leão | J. Anthony Scott | Hanna Nohynek | Katherine L. O'Brien

In 2003 the World Health Organization (WHO) convened a working group and published a set of standard methods for studies measuring nasopharyngeal carriage of Streptococcus pneumoniae (the pneumococcus). The working group recently reconvened under the auspices of the WHO and updated the consensus standard methods. These methods describe the collection, transport and storage of nasopharyngeal samples, as well as provide recommendations for the identification and serotyping of pneumococci using culture and non-culture based approaches. We outline the consensus position of the working group, the evidence supporting this position, areas worthy of future research, and the epidemiological role of carriage studies. Adherence to these methods will reduce variability in the conduct of pneumococcal carriage studies undertaken in the context of pneumococcal vaccine trials, implementation studies, and epidemiology studies more generally so variability in methodology does not confound the interpretation of study findings. © 2013 Elsevier Ltd.

Alina Sadaf | Jennifer L. Richards | Jason Glanz | Daniel A. Salmon | Saad B. Omer

Unvaccinated individuals pose a public health threat to communities. Research has identified many factors associated with parental vaccine refusal and hesitancy toward childhood and adolescent immunizations. However, data on the effectiveness of interventions to address parental refusal are limited. We conducted a systematic review of four online databases to identify interventional studies.We used criteria recommended by the WHO's Strategic Advisory Group of Experts on immunization (SAGE) for the quality assessment of studies. Intervention categories and outcomes were evaluated for each body of evidence and confidence in overall estimates of effect was determined. There is limited evidence to guide implementation of effective strategies to deal with the emerging threat of parental vaccine refusal. There is a need for appropriately designed, executed and evaluated intervention studies to address this gap in knowledge. © 2013 Elsevier Ltd.

L. J. Anderson | P. R. Dormitzer | D. J. Nokes | R. Rappuoli | A. Roca | B. S. Graham

Although RSV has been a high priority for vaccine development, efforts to develop a safe and effective vaccine have yet to lead to a licensed product. Clinical and epidemiologic features of RSV disease suggest there are at least 4 distinct target populations for vaccines, the RSV naïve young infant, the RSV naïve child ≥6 months of age, pregnant women (to provide passive protection to newborns), and the elderly. These target populations raise different safety and efficacy concerns and may require different vaccination strategies. The highest priority target population is the RSV naïve child. The occurrence of serious adverse events associated with the first vaccine candidate for young children, formalin inactivated RSV (FI-RSV), has focused vaccine development for the young RSV naïve child on live virus vaccines. Enhanced disease is not a concern for persons previously primed by a live virus infection. A variety of live-attenuated viruses have been developed with none yet achieving licensure. New live-attenuated RSV vaccines are being developed and evaluated that maybe sufficiently safe and efficacious to move to licensure. A variety of subunit vaccines are being developed and evaluated primarily for adults in whom enhanced disease is not a concern. An attenuated parainfluenza virus 3 vector expressing the RSV F protein was evaluated in RSV naïve children. Most of these candidate vaccines have used the RSV F protein in various vaccine platforms including virus-like particles, nanoparticles, formulated with adjuvants, and expressed by DNA or virus vectors. The other surface glycoprotein, the G protein, has also been used in candidate vaccines.We now have tools to make and evaluate a wide range of promising vaccines. Costly clinical trials in the target population are needed to evaluate and select candidate vaccines for advancement to efficacy trials. Better data on RSV-associated mortality in developing countries, better estimates of the risk of long term sequelae such as wheezing after infection, better measures of protection in target populations, and data on the costs and benefits of vaccines for target populations are needed to support and justify funding this process. Addressing these challenges and needs should improve the efficiency and speed of achieving a safe and effective, licensed RSV vaccine. © 2013 Elsevier Ltd.

Anneke Steens | Marianne A.Riise Bergsaker | Ingeborg S. Aaberge | Karin Rønning | Didrik F. Vestrheim

The introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in the childhood immunisation programme in Norway in 2006 substantially decreased the incidence of vaccine-type (VT) invasive pneumococcal disease (IPD) in all age groups. Additionally, a slight increase in the non-vaccine (NVT) serotype IPD incidence (serotype replacement) was observed. After replacing PCV7 with PCV13 in 2011, a further decrease in IPD incidence is expected. However, the protection by the six additional serotypes opens new nasopharyngeal niches for colonisation, which favours conditions for serotype replacement. Close monitoring of IPD therefore remains important in order to quickly detect changes. In this observational retrospective population-based cohort study we used data notified nationally between 1 January 2004 and 31 December 2012 to determine the VT- and NVT-IPD incidences. The diversity in serotype distribution per year was analysed using the Simpson's index of diversity. Immunisation history of young children was obtained from the Norwegian Vaccination Registry to determine vaccine failure. The incidence of VT-IPD decreased in the targeted ( < 5 years) and non-targeted (≥5) age groups since PCV7 introduction and further decreased after the replacement with PCV13. Only two cases of vaccine failure were identified. This indicates very high effectiveness of the 2. +. 1 schedules with PCV7 or PCV13 and suggests that non-vaccinated individuals profit through indirect protection. The decrease in incidence of PCV7-IPD in non-targeted age groups became larger in later years, indicating a lag phase for the indirect effects, and suggests that the indirect protection of PCV13 will increase in coming years. The incidence of some NVT, specifically serotypes 23B and 15A, increased after PCV13 introduction. This coincided with an increased Simpson's index of diversity in the targeted age group. As this suggests that serotype replacement is again occurring, continues monitoring of IPD is important so that adaptations to vaccine recommendations can be promptly issued. © 2013 Elsevier Ltd.

F. Xavier Bosch | Thomas R. Broker | David Forman | Anna Barbara Moscicki | Maura L. Gillison | John Doorbar | Peter L. Stern | Margaret Stanley | Marc Arbyn | Mario Poljak | Jack Cuzick | Philip E. Castle | John T. Schiller | Lauri E. Markowitz | William A. Fisher | Karen Canfell | Lynette A. Denny | Eduardo L. Franco | Marc Steben | Mark A. Kane | Mark Schiffman | Chris J.L.M. Meijer | Rengaswamy Sankaranarayanan | Xavier Castellsagué | Jane J. Kim | Maria Brotons | Laia Alemany | Ginesa Albero | Mireia Diaz | Silvia de Sanjosé

Infection with human papillomavirus (HPV) is recognized as one of the major causes of infection-related cancer worldwide, as well as the causal factor in other diseases. Strong evidence for a causal etiology with HPV has been stated by the International Agency for Research on Cancer for cancers of the cervix uteri, penis, vulva, vagina, anus and oropharynx (including base of the tongue and tonsils). Of the estimated 12.7 million new cancers occurring in 2008 worldwide, 4.8% were attributable to HPV infection, with substantially higher incidence and mortality rates seen in developing versus developed countries. In recent years, we have gained tremendous knowledge about HPVs and their interactions with host cells, tissues and the immune system; have validated and implemented strategies for safe and efficacious prophylactic vaccination against HPV infections; have developed increasingly sensitive and specific molecular diagnostic tools for HPV detection for use in cervical cancer screening; and have substantially increased global awareness of HPV and its many associated diseases in women, men, and children. While these achievements exemplify the success of biomedical research in generating important public health interventions, they also generate new and daunting challenges: costs of HPV prevention and medical care, the implementation of what is technically possible, socio-political resistance to prevention opportunities, and the very wide ranges of national economic capabilities and health care systems. Gains and challenges faced in the quest for comprehensive control of HPV infection and HPV-related cancers and other disease are summarized in this review. The information presented may be viewed in terms of a reframed paradigm of prevention of cervical cancer and other HPV-related diseases that will include strategic combinations of at least four major components: 1) routine introduction of HPV vaccines to women in all countries, 2) extension and simplification of existing screening programs using HPV-based technology, 3) extension of adapted screening programs to developing populations, and 4) consideration of the broader spectrum of cancers and other diseases preventable by HPV vaccination in women, as well as in men. Despite the huge advances already achieved, there must be ongoing efforts including international advocacy to achieve widespread-optimally universal-implementation of HPV prevention strategies in both developed and developing countries.This article summarizes information from the chapters presented in a special ICO Monograph '. Comprehensive Control of HPV Infections and Related Diseases' Vaccine Volume 30, Supplement 5, 2012. Additional details on each subtopic and full information regarding the supporting literature references may be found in the original chapters. © 2013 Elsevier Ltd.

Ainhoa Arbues | Juan I. Aguilo | Jesus Gonzalo-Asensio | Dessislava Marinova | Santiago Uranga | Eugenia Puentes | Conchita Fernandez | Alberto Parra | Pere Joan Cardona | Cristina Vilaplana | Vicente Ausina | Ann Williams | Simon Clark | Wladimir Malaga | Christophe Guilhot | Brigitte Gicquel | Carlos Martin

The development of a new tuberculosis vaccine is an urgent need due to the failure of the current vaccine, BCG, to protect against the respiratory form of the disease. MTBVAC is an attenuated Mycobacterium tuberculosis vaccine candidate genetically engineered to fulfil the Geneva consensus requirements to enter human clinical trials. We selected a M. tuberculosis clinical isolate to generate two independent deletions without antibiotic-resistance markers in the genes phoP, coding for a transcription factor key for the regulation of M. tuberculosis virulence, and fadD26, essential for the synthesis of the complex lipids phthiocerol dimycocerosates (DIM), one of the major mycobacterial virulence factors. The resultant strain MTBVAC exhibits safety and biodistribution profiles similar to BCG and confers superior protection in preclinical studies. These features have enabled MTBVAC to be the first live attenuated M. tuberculosis vaccine to enter clinical evaluation. © 2013 Elsevier Ltd.

Kirsty Le Doare | Paul T. Heath

Streptococcus agalactiae (group B streptococcus (GBS)), remains the leading cause of neonatal sepsis and meningitis in many countries and an important cause of disease in pregnant women, immunocompromised adults and the elderly. Intrapartum antibiotic strategies have reduced the incidence of early-onset neonatal GBS where applied, but have had no impact on late onset GBS infection and only a limited impact on disease in pregnant women. In low/middle income settings, the disease burden remains uncertain although in several countries of Southern Africa appears comparable to that of high-income countries. Disease may be rapidly fulminating and cases therefore missed before appropriate samples are obtained. This may lead to significant underestimation of the true burden and be a particular issue in many African and Asian countries; comprehensive epidemiological data from such countries are urgently required.The available data suggest that the serotype distribution of GBS isolates is similar in Africa, Western Pacific, Europe, the Americas and the Eastern Mediterranean regions and has not changed over the past 30 years . Five serotypes (Ia, Ib, II, III, V) account for the majority of disease; conjugate vaccines including some or all of these serotypes therefore hold great promise for preventing this important disease. © 2013 Elsevier Ltd.

K. E. Wiley | Y. Zuo | K. K. Macartney | P. B. McIntyre

Background: The relative contribution of different categories of contact in transmitting pertussis to very young infants, who experience the most severe morbidity, is the most important single factor determining the likely benefit of pertussis vaccination of their close contacts (the " cocooning" strategy). Objective: To identify, evaluate the quality of and summarise existing data on potential sources of infant pertussis infection in high income countries, focussing on infants under 6 months old.Data sources: Online databases MEDLINE and EMBASE. Additional studies were identified from the reference lists of relevant articles.Study selection and analysis: Study quality was evaluated by standardised criteria, based on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement. Pooled estimates of the proportion of pertussis cases attributable to various contact sources were calculated using data from the highest quality studies. Results: Nine studies met the inclusion criteria; seven included data on contacts of hospitalised infants less than 6 months old. Case definitions and methods of contact ascertainment were variable. Most identified sources were from the household, of which 39% (95%CI 33-45%) were mothers, 16% (95%CI 12-21%) fathers, and 5% (95%CI 2-10%) grandparents. Estimates for siblings (16-43%) and non-household contacts (4-22%) were more heterogeneous. For 32-52% of infant cases, no source was identified. Asymptomatic pertussis infection was found in 8-13% of contacts evaluated. Conclusions: These data suggest that the greatest potential impact of pertussis vaccination of adults to prevent severe disease in young infants comes from vaccinating mothers, followed by fathers, with grandparents having a minor role. Siblings varied in importance and, given recent data regarding waning immunity in vaccinated children, need further study. Non-household sources are also well documented, highlighting the potential limitations of the cocoon strategy to prevent severe infant disease. © 2012 Elsevier Ltd.

Lisa A. Jackson | Alejandra Gurtman | Kathryn Rice | Karlis Pauksens | Richard N. Greenberg | Thomas R. Jones | Daniel A. Scott | Emilio A. Emini | William C. Gruber | Beate Schmoele-Thoma

Background: The currently recommended single dose of the 23-valent pneumococcal free polysaccharide vaccine (PPSV23) for adults 65 years of age and older does not provide extended protection into older age. This reflects a significant unmet medical need for alternative strategies to protect older adults against pneumococcal infection, which may be met by the 13-valent polysaccharide conjugate vaccine (PCV13). Methods: We performed a randomized, modified double-blind trial in 936 adults aged 70 years and older who had previously received PPSV23 at least 5 years before study entry and were now vaccinated with PCV13 or PPSV23. At 1 year after enrollment, all subjects received a follow-on dose of PCV13. Anti-pneumococcal opsonophagocytic activity (OPA) titers were measured before and at 1 month after each vaccination. Results: Following the enrollment vaccination, OPA titers were significantly greater in the PCV13 group compared to the PPSV23 group for 10 of the 12 serotypes common to both vaccines and to serotype 6A which is unique to PCV13. Responses were noninferior for the other 2 common serotypes. Responses to PCV13 given at 1 year were generally lower in the group that received PPSV23 at enrollment. Conclusion: In adults aged 70 years and older previously vaccinated with PPSV23, PCV13 was significantly more immunogenic than PPSV23 for most of the common serotypes and for serotype 6A. The OPA responses after a follow-on dose of PCV13 one year later indicate that a prior dose of PPSV23, but not PCV13, diminishes the response to the subsequent administration of PCV13. © 2013 The Authors.

James J. Norman | Jaya M. Arya | Maxine A. McClain | Paula M. Frew | Martin I. Meltzer | Mark R. Prausnitz
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