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Dengue fever is an infectious disease caused by the dengue virus (DENV), an RNA Flavivirus transmitted by the mosquitoes Aedes aegypti and Aedes albopictus widespread in tropical, subtropical and also temperate regions. Symptoms range from a simple cold to a severe, life-threatening haemorrhagic fever. According to the WHO, it affects around 390 million people per year. No antiviral treatment for DENV is available, and the Dengvaxia vaccine is only intended for people over 9 years of age who have contracted dengue one time in the past, and shows serotype-specific effectiveness. There is therefore a crying need to discover new molecules with antiviral power against flaviviruses. The present study was carried out to evaluate the anti-DENV activities and cytotoxicity of triazenes obtained by diazocopulation. Some triazenes were highly cytotoxic (16, and 25) to hepatocarcinoma Huh7 cells, whereas others displayed strong anti-DENV potential. The antiviral activity ranged from EC 50  = 7.82 µM to 48.12 µM in cellulo, with a selectivity index (CC 50 /EC 50 ) greater than 9 for two of the compounds (10, and 20). In conclusion, these new triazenes could serve as a lead to develop and optimize drugs against DENV., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of COVID-19. Though many COVID-19 vaccines have been developed, most of them are delivered via intramuscular injection and thus confer relatively weak mucosal immunity against the natural infection. Virus-Like Particles (VLPs) are self-assembled nanostructures composed of key viral structural proteins, that mimic the wild-type virus structure but are non-infectious and non-replicating due to the lack of viral genetic material. In this study, we efficiently generated SARS-CoV-2 VLPs by co-expressing the four SARS-CoV-2 structural proteins, specifically the membrane (M), small envelope (E), spike (S) and nucleocapsid (N) proteins. We show that these proteins are essential and sufficient for the efficient formation and release of SARS-CoV-2 VLPs. Moreover, we used lentiviral vectors to generate human cell lines that stably produce VLPs. Because VLPs can bind to the virus natural receptors, hence leading to entry into cells and viral antigen presentation, this platform could be used to develop novel vaccine candidates that are delivered intranasally., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Amaryllidaceae alkaloids (AAs) are a structurally diverse family of alkaloids recognized for their many therapeutic properties, such as antiviral, anti-cholinesterase, and anticancer properties. Norbelladine and its derivatives, whose biological properties are poorly studied, are key intermediates required for the biosynthesis of all ~650 reported AAs. To gain insight into their therapeutic potential, we synthesized a series of O-methylated norbelladine-type alkaloids and evaluated their cytotoxic effects on two types of cancer cell lines, their antiviral effects against the dengue virus (DENV) and the human immunodeficiency virus 1 (HIV-1), and their anti-Alzheimer’s disease (anti-cholinesterase and -prolyl oligopeptidase) properties. In monocytic leukemia cells, norcraugsodine was highly cytotoxic (CC50 = 27.0 μM), while norbelladine was the most cytotoxic to hepatocarcinoma cells (CC50 = 72.6 μM). HIV-1 infection was impaired only at cytotoxic concentrations of the compounds. The 3,4-dihydroxybenzaldehyde (selectivity index (SI) = 7.2), 3′,4′-O-dimethylnorbelladine (SI = 4.8), 4′-O-methylnorbelladine (SI > 4.9), 3′-O-methylnorbelladine (SI > 4.5), and norcraugsodine (SI = 3.2) reduced the number of DENV-infected cells with EC50 values ranging from 24.1 to 44.9 μM. The O-methylation of norcraugsodine abolished its anti-DENV potential. Norbelladine and its O-methylated forms also displayed butyrylcholinesterase-inhibition properties (IC50 values ranging from 26.1 to 91.6 μM). Altogether, the results provided hints of the structure−activity relationship of norbelladine-type alkaloids, which is important knowledge for the development of new inhibitors of DENV and butyrylcholinesterase.

Ten Amaryllidaceae alkaloids (AAs) were isolated for the first time from Pancratium maritimum collected in Calabria region, Italy. They belong to different subgroups of this family and were identified as lycorine, which is the main alkaloid, 9-O-demethyllycorine, haemanthidine, haemanthamine, 11-hydroxyvittatine, homolycorine, pancracine, obliquine, tazettine and vittatine. Haemanthidine was isolated as a scalar mixture of two 6-epimers, as already known also for other 6-hydroxycrinine alkaloids, but for the first time they were separated as 6,11-O,O′-di-p-bromobenzoyl esters. The evaluation of the cytotoxic and antiviral potentials of all isolated compounds was undertaken. Lycorine and haemanthidine showed cytotoxic activity on Hacat cells and A431 and AGS cancer cells while, pancracine exhibited selective cytotoxicity against A431 cells. We uncovered that in addition to lycorine and haemanthidine, haemanthamine and pancracine also possess antiretroviral abilities, inhibiting pseudotyped human immunodeficiency virus (HIV)−1 with EC50 of 25.3 µM and 18.5 µM respectively. Strikingly, all the AAs isolated from P. maritimum were able to impede dengue virus (DENV) replication (EC50 ranged from 0.34−73.59 µM) at low to non-cytotoxic concentrations (CC50 ranged from 6.25 µM to >100 µM). Haemanthamine (EC50 = 337 nM), pancracine (EC50 = 357 nM) and haemanthidine (EC50 = 476 nM) were the most potent anti-DENV inhibitors. Thus, this study uncovered new antiviral properties of P. maritimum isolated alkaloids, a significant finding that could lead to the development of new therapeutic strategies to fight viral infectious diseases.

Background: Standing on a foam surface is used to investigate how aging affect the ability to keep balance when somatosensory inputs from feet soles become unreliable. However, since standing on foam also affects the efficacy of postural adjustments, the respective contributions of sensory and motor components are impossible to separate. This study tested the hypothesis that these components can be untangled by comparing changes of center of pressure (CoP) parameters induced by standing on a foam pad vs. a novel vibration (VIB) platform developed by our team and targeting feet soles' mechanoreceptors. Methods: Bipedal postural control of young ( n = 20) and healthy elders ( n = 20) was assessed while standing barefoot on a force platform through 3 randomized conditions: (1) Baseline (BL); (2) VIB; and (3) Foam. CoP Amplitude and Velocity in the antero-posterior/medio-lateral (AP/ML) directions and COP Surface were compared between conditions and groups. Findings: Both VIB and Foam increased CoP parameters compared to BL, but Foam had a significantly greater impact than VIB for both groups. Young and Old participants significantly differed for all three Conditions. However, when correcting for BL levels of postural performance, VIB-related increase of COP parameters was no longer different between groups, conversely to Foam. Interpretation: Although both VIB and Foam highlighted age-related differences of postural control, their combined use revealed that "motor" and "sensory" components are differently affected by aging, the latter being relatively unaltered, at least in healthy/active elders. The combined used of these methods could provide relevant knowledge to better understand and manage postural impairments in the aging population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lauzier, Kadri, Bouchard, Bouchard, Gaboury, Gagnon, Girard, Larouche, Robert, Lapointe, da Silva and Beaulieu.)

Objective: Lumbopelvic pain (LBPP) affects 45% to 81% of pregnant women, and 25% to 43% of these women report persistent LBPP beyond 3 months after giving birth. The objective of this study was to investigate the association of physical activity, weight status, anxiety, and evolution of LBPP symptoms in postpartum women., Methods: This was a prospective observational cohort study with 3 time-point assessments: baseline (T0), 3 months (T3), and 6 months (T6). Women with persistent LBPP 3 to 12 months after delivery were recruited. At each time point, pain disability was assessed with the Pelvic Girdle Questionnaire and the Oswestry Disability Index (ODI), physical activity with Fitbit Flex monitors, and anxiety with the French-Canadian version of the State-Trait Anxiety Inventory. Weight was recorded using a standardized method. Pain intensity (numerical rating scale, 0-100) and frequency were assessed using a standardized text message on a weekly basis throughout the study., Results: Thirty-two women were included (time postpartum: 6.6 ± 2.0 months; maternal age: 28.3 ± 3.8 years; body weight: 72.9 ± 19.1 kg), and 27 completed the T6 follow-up. Disability, pain intensity, and pain frequency improved at T6 (P < .001). Participants lost a mean of 1.9 ± 4.5 kg at T6, and this weight loss was correlated with reduction in LBPP intensity (r = 0.479, P = .011) and LBPP frequency (r = 0.386, P = .047), Pelvic Girdle Questionnaire score (r = 0.554, P = .003), and ODI score (r = 0.494, P = .009). Improvement in ODI score at T6 was correlated with the number of inactive minutes at T3 (r = -0.453, P = .026) and T6 (r = -0.457, P = .019), and with daily steps at T6 (r = 0.512, P = .006)., Conclusion: Weight loss is associated with positive LBPP symptom evolution beyond 3 months postpartum, and physical activity is associated with reduction in pain disability., (Copyright © 2020. Published by Elsevier Inc.)

Aim: To further the understanding of the pathophysiological mechanisms underlying tension-type headache (TTH) by comparing the endurance and strength of neck extensor muscles under acute muscle fatigue in participants with TTH and asymptomatic participants., Methods: We conducted a cross-sectional analysis of neck extensor muscle performance. Asymptomatic participants and participants with TTH were recruited via social media platforms and from the Université du Québec à Trois-Rivières community and employees. A total of 44 participants with TTH and 40 asymptomatic participants took part in an isometric neck extensor endurance task performed at 60% of their maximum voluntary contraction. Inclusion criteria for the headache group were to be older than 18 years old and to fulfil the International Headache Society classification's criteria for either frequent episodic or chronic TTH. Clinical (self-efficacy, anxiety, neck disability and kinesiophobia) and physical parameters (neck extensors maximum voluntary contraction, endurance time, muscle fatigue) as well as characteristics of headache episodes (intensity, frequency and associated disability) were collected for all participants. Surface electromyography was used to document upper trapezius, splenius capitis and sternocleidomastoids muscle activity and muscle fatigue., Results: Both groups displayed similar neck extensor muscle endurance capacity with a mean difference of 6.2 s (p>0.05) in favour of the control group (control=68.1±32.3; TTH=61.9±20.1). Similarly, participants in the headache group showed comparable neck extensor muscle strength (95.9±30.4 N) to the control group (111.3±38.7 N). Among participants with TTH, those scoring as severely incapacitated by headaches were the ones with higher neck-related disability (F[1,44]=10.77; p=0.002), the more frequent headache episodes (F[1,44]=6.70; p=0.01) and higher maximum headache intensity (F[1,44]=10.81; p=0.002)., Conclusion: A fatigue task consisting of isometric neck extension cannot efficiently differentiate participants with TTH from asymptomatic participants., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Pain in the pelvic girdle area is commonly reported during pregnancy and the postpartum period, and its impact on quality of life is considerable. The Pelvic Girdle Questionnaire (PGQ), developed in 2011 in Norway, is the only condition-specific tool assessing pelvic girdle pain-related symptoms and disability. The questionnaire was recently translated and adapted for the French-Canadian population. The objective of this study was to assess the measurement properties of the previously translated French-Canadian PGQ., Methods: Eighty-two women with pelvic girdle pain were included in this validation study. The French-Canadian PGQ, pain intensity Numeric Rating Scale, and Oswestry Disability Index were completed by participants at baseline, 48 hours later, and 3 to 6 months later to assess test-retest reliability, construct validity, responsiveness, floor and ceiling effects, and internal consistency., Results: Reliability analyses indicated an intraclass correlation coefficient of 0.841 (95% confidence interval [CI] 0.750-0.901) for the global score. Construct validity analyses indicated a Spearman rank correlation coefficient of 0.696 with the Oswestry Disability Index. Responsiveness analyses identified an effect size of 0.908 (95% CI 0.434-1.644) and an area under the receiver operating characteristics curve of 0.823 (95% CI 0.692-0.953). There was no floor or ceiling effect, and internal consistency analyses indicated a Cronbach α of .933 for the activity subscale and .673 for the symptom subscale., Conclusion: Overall, the French-Canadian version of the PGQ is reliable, valid, and responsive, suggesting that it can be implemented in both research and clinical settings to assess functional limitations in pregnant and postpartum women., (Copyright © 2018. Published by Elsevier Inc.)

Aim The purpose of this systematic literature review is to assess the benefits of workplace-based occupational therapies and interventions, including acute and preventive medication, on headache intensity and frequency, related disability as well as work-related outcomes. Methods A search of the literature was conducted in PubMed, MEDLINE, Cochrane library, CINAHL and Embase using terms related to headache, workplace and occupational health. The Cochrane Collaboration's risk of bias assessment tool was used on individual studies to assess internal validity and the Grading of Recommendations Assessment, Development, and Evaluation system was applied to studies by clinical outcome and used to rate quality of evidence. Results Fifteen articles were included in the systematic review. None of them were classified as low risk of bias according to the Cochrane Collaboration's tool for assessing risk of bias. This systematic review found preliminary low-quality evidence suggesting that exercise and acupuncture can reduce workers' headache pain intensity, frequency and related disability. Conclusion Although this systematic review provided preliminary low evidence in favour of work-based intervention, studies with more rigorous designs and methodologies are needed to provide further evidence of the effectiveness of workplace-based headache management strategies.

Objective: The Pelvic Girdle Questionnaire (PGQ) is the only condition-specific tool assessing activity limitations and symptoms for those with pelvic girdle pain (PGP). It is simple to administer and can be used in research and clinical settings during pregnancy and postpartum periods; however, there currently is no version for the French-Canadian population. The aim of this study was to translate and culturally adapt the PGQ for the French-Canadian population., Methods: The French-Canadian translation and adaptation of the PGQ was completed following a 4-stage approach: (1) forward translation, (2) synthesis, (3) expert committee review, and (4) testing of the prefinal version of the questionnaire. The testing stage was conducted with a cohort of 34 women, aged 18 to 45 years, who experienced PGP over the span of pregnancy or during the first year postpartum., Results: The global understanding of the PGP concept was rated as either "Fair" (41.2%) or "Good" (32.4%) by the majority of participants, which led to the consensual decision to add an illustration of the pelvic girdle region to the final version of the French-Canadian PGQ. Only 1 item ("Has your leg/have your legs given way?") was reported as unclear by 12 participants (35.3%). The expert committee unanimously agreed to add a brief explanation of the term "given way" to the final version to ensure proper understanding of the question., Conclusions: The current study yielded a satisfactory French-Canadian translation of the PGQ., (Copyright © 2016. Published by Elsevier Inc.)

The 2015 Cent Gardes Conference on HIV vaccines took place on October 25-27 at the Merieux Foundation Conference Center in Veyrier du Lac, near Annecy, France. The meeting reviewed progress in the development of HIV vaccines and identified new directions of future research. The field has advanced incrementally over the past year but major progress will require additional information from new clinical trials. In this article, we review the presentations on humoral immune responses to HIV, and highlight the difficulty of eliciting broadly neutralizing antibodies by vaccination. Advances in cellular immunity for HIV prevention will be reviewed separately, in a following article., (Copyright © 2016.)

Despite remarkable advances in HIV treatment, responsible for the saving of thousands of lives, the design of an effective HIV vaccine able to prevent infectivity and stop the AIDS epidemic remains a priority for health care. Publication of the first partly efficacious large-scale HIV vaccine trial in Thaïland in 2009 has durably transformed the HIV vaccine landscape, bringing in new hopes that an HIV protective vaccine may be doable. New correlates of protection have been identified, new HIV broadly neutralizing antibodies are regularly reported, and the importance of T-effector memory cells in protection has definitely been demonstrated. In this review, we explore the difficulties encountered in designing an HIV vaccine, relate the long road already traveled, with its many failures, describe the main vaccine strategies currently under test, which explain the current moderate optimism in HIV vaccine research.

Purpose of Review: To review the status of HIV vaccine development, Recent Findings: Since the discovery of HIV-1 in the early 1980s considerable effort has been exerted to develop a prophylactic vaccine, with relatively meagre results. The absence of natural immunity has proven to be a major stumbling block in identifying a mechanism of protection. However, many different animal models have contributed to our knowledge of the pathogenesis of infection and of the variety of antibody and cellular responses that are induced by the virus. The knowledge created by the studies in nonhuman primates, although important, has not necessarily been proven applicable in humans and thus an effective vaccine has been elusive. The combined lack of a fully predictive animal model ('mice lie and monkeys exaggerate') and lack of defined markers of immune protection against HIV-1 necessitate that HIV vaccines be tested directly for efficacy in phase IIb/III efficacy trials in human volunteers at risk. A trial conducted in Thailand showed moderate but significant protection against infection., Summary: The process of HIV vaccine development is slow, costly and tedious. However, recent preclinical and clinical results have fortunately been a source of renewed optimism in the field.

The development of a safe, effective and globally affordable HIV vaccine offers the best hope for the future control of the HIV-1 pandemic. Since 1987, scores of candidate HIV-1 vaccines have been developed which elicited varying degrees of protective responses in nonhuman primate models, including DNA vaccines, subunit vaccines, live vectored recombinant vaccines and various prime-boost combinations. Four of these candidate vaccines have been tested for efficacy in human volunteers, but, to the exception of the recent RV144 Phase III trial in Thailand, which elicited a modest but statistically significant level of protection against infection, none has shown efficacy in preventing HIV-1 infection or in controlling virus replication and delaying progression of disease in humans. Protection against infection was observed in the RV144 trial, but intensive research is needed to try to understand the protective immune mechanisms at stake. Building-up on the results of the RV144 trial and deciphering what possibly are the immune correlates of protection are the top research priorities of the moment, which will certainly accelerate the development of an highly effective vaccine that could be used in conjunction with other HIV prevention and treatment strategies. This article reviews the state of the art of HIV vaccine development and discusses the formidable scientific challenges met in this endeavor, in the context of a better understanding of the immunopathogenesis of the disease., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

On February 17-18, 2010, the World Health Organization (WHO) convened the 6th meeting on the "Evaluation of pandemic influenza vaccines in clinical trials" to review the progress made on new A (H1N1) 2009 vaccines and prototype H5N1 vaccines and their evaluation in clinical trials. A number of vaccine types were reviewed, including classical egg-derived and cell culture-derived inactivated vaccines, such as split virus or whole-virion vaccines, and live-attenuated vaccines (LAIV), as well as vaccines developed using new technologies. The amount of antigen needed, the effect of adjuvants and the number of doses required to induce adequate antibody responses in various populations, together with the issue of safety of the vaccines, were major topics of the meeting. The effectiveness of H1N1 vaccines and the need for standardization of vaccine potency tests were also discussed. Independent of the vaccine type and the presence or absence of an adjuvant, all A (H1N1) 2009 vaccines were well tolerated, eliciting only mild to moderate local or systemic reactions. For most vaccines tested, a single dose was sufficient to elicit a potentially protective antibody response in the majority of vaccinees >10 years of age. However, a second dose of vaccine was needed to boost immune responses in infants and toddlers 6 months to 3 years of age and, with some vaccines, in children aged 3-9 years., (Copyright © 2010 World Health Organization. Published by Elsevier Ltd.. All rights reserved.)

In March and early April 2009 a new swine-origin influenza virus (S-OIV), A (H1N1), emerged in Mexico and the USA. The virus quickly spread worldwide through human-to-human transmission. In view of the number of countries and communities which were reporting human cases, the World Health Organization raised the influenza pandemic alert to the highest level (level 6) on June 11, 2009. The propensity of the virus to primarily affect children, young adults and pregnant women, especially those with an underlying lung or cardiac disease condition, and the substantial increase in rate of hospitalizations, prompted the efforts of the pharmaceutical industry, including new manufacturers from China, Thailand, India and South America, to develop pandemic H1N1 influenza vaccines. All currently registered vaccines were tested for safety and immunogenicity in clinical trials on human volunteers. All were found to be safe and to elicit potentially protective antibody responses after the administration of a single dose of vaccine, including split inactivated vaccines with or without adjuvant, whole-virion vaccines and live-attenuated vaccines. The need for an increased surveillance of influenza virus circulation in swine is outlined., (Copyright 2010. Published by Elsevier Ltd.)

The field of vaccines and vaccinology has seen remarkable progress during the past 20 years. Many vaccines, however, still need to be improved, either because the protection they provide is relatively short-lived and would greatly benefit from the development of booster formulations (as is the case for tuberculosis), or because they only cover part of the many serotypes of the pathogen that causes the disease (rotaviruses, papillomaviruses, or Streptococcus pneumoniae). In addition, still many diseases lack a proper preventive vaccine, such as AIDS, hepatitis C, malaria, viral pneumonias, croup and bronchiolitis, dengue fever, leishmaniasis, Staphylococcus aureus, groups A and B Streptococcus, Shigellas and enterotoxigenic Escherichia coli, to only name a few. These are the current targets of vaccines under development, a great many of which will hopefully reach the market within the coming 10 years. The development of preventive vaccines against chronic diseases such as AIDS and hepatitis C will probably require more time, due to basic science complexities to be overcome first. It is likely that the future will also see an emphasis on therapeutic vaccines targeted against noninfectious diseases such as cancers (lung, skin, prostate, etc) and metabolic or neurologic diseases (atherosclerosis, Alzheimer's disease). This review will focus on examples of preventive vaccines under development that target infectious diseases with a heavy global burden on public health.

The development of an HIV/AIDS vaccine faces formidable challenges related to the high genetic variability of the virus which has developed potent escape mechanisms to dodge the immune responses of the host, while maintaining the immune system in a permanent state of activation that rapidly leads to T cell exhaustion. Our total lack of knowledge on potential immune correlates of protection, our inability to elicit potent broadly neutralizing anti-HIV antibodies by active immunization added to the limitations with the existing animal models are other obstacles to overcome. The field met with its first failure 5 years ago when a gp120-based subunit vaccine showed no protection against HIV infection in two Phase III trials in the USA and Thailand. It recently met with its second failure when the Merck "STEP" trial had to be prematurely interrupted. The trial was a Phase IIb study of an Adenovirus 5 (Ad5)-HIV vaccine meant to elicit a cellular immune response, essentially HIV-specific CD8+ CTLs, to control viremia in the vaccinees who happened to become infected. Not only did the vaccine fail to control the viral loads in the HIV-infected vaccinees, but unexpectedly the number of HIV infections observed in adenovirus-pre-immune volunteers was significantly higher in the vaccine group than in the placebo group. This does not imply that T cell vaccines have no future but illustrates the limitations and risks of that approach. It also suggests that current assays that measure T cell responses are inadequate to assess CTL functionality. Taking into account the failure of these first two generations of HIV/AIDS vaccines, the development of a third generation vaccine is being considered, aiming at setting up a dual humoral and cellular immune barrier to HIV at the mucosal site of entry of the virus.

Encouraged by the success of the global smallpox eradication certified in 1980, the global poliomyelitis eradication program was launched in 1988 by the World Health Organization (WHO). In addition to routine polio immunization included in the Expanded Program of Immunization (EPI), two major activities were planned: mass polio vaccination campaigns and surveillance of all cases of acute flaccid paralysis. In 2000, the disease had been eliminated from most countries in the world. However, as of 2002, the community acceptance of vaccination was endangered in some countries by rumors about assumed adverse effects of oral polio vaccine. The rejection of polio immunization provided a worrying resurgence of polio in Northern Nigeria, followed by re-infection of 21 countries, whereas resurgence of the disease also was observed in Northern India. Supplementary vaccination activities were resumed, additional resources were mobilized and, in 2007, most re-infected countries became polio-free again. Today, polio remains endemic in only four countries. The goal of global polio eradication has now been set at 2010, but doubts have been expressed about the feasibility of its achievement.

HIV vaccine research is at a crossroads carefully contemplating on the next path. The unexpected results of the Merck vaccine trial, while providing a stunning blow to a field in dire need of a protective vaccine, has also raised several fundamental questions regarding the candidate immunogen itself, preexisting immunity to vaccine vectors, surrogate assays and animal models used for assessing preclinical protective responses, as well as relevant endpoints to be measured in a clinical trial. As a result, the research community is faced with the daunting task of identifying novel vaccine concepts and products to continue the search. This review highlights and addresses some of the scientific and practical concerns.

After over 20 years of research and development (R&D) and more than 85 clinical trials using various candidate vaccines, there has been little progress in research for a vaccine against HIV/AIDS. This disappointing result raises serious doubts as to whether an effective HIV/AIDS vaccine will be available within a reasonable time frame. There are three main obstacles. The first is that the virus promptly enters into the genome of effector memory T-cells that then constitute an infection reservoir from which the virus cannot be dislodged. The second obstacle involves the genetic hyper-variability of the virus that can easily dodge host immune defenses by mutating. The third obstacle is that we are still unable to induce antibodies able to neutralize wild strains of the virus and block infection early. Current vaccines are designed to induce cellular immune responses - mostly of the CD8+ cytotoxic T cell (CTL) type - in the hope of limiting the clinical consequences of infection by reducing the rate of virus multiplication and decreasing virus load in recently infected persons. This strategy has led to development of numerous live attenuated vaccines using a wide variety of viral or bacterial vectors. These vaccines are currently being tested either singly or in various prime-boost combinations using several of these vaccines or DNA vaccines. The efficacy of these vaccination techniques in humans remains to be determined.

The last several years have seen significant progress in the development of vaccines against malaria. Most recently, proof-of-concept of vaccine-induced protection from malaria infection and disease was demonstrated in African children. Pursued by various groups and on many fronts, several other candidate vaccines are in early clinical trials. Yet, despite the optimism and promise, an effective malaria vaccine is not yet available, in part because of the lack of understanding of the types of immune responses needed for protection, added to the difficulty of identifying, selecting and producing the appropriate protective antigens from a parasite with a genome of well over five thousand genes and to the frequent need to enhance the immunogenicity of purified antigens through the use of novel adjuvants or delivery systems. Insufficient clinical trial capacity and normative research functions such as local ethical committee reviews also contribute to slow down the development process. This article attempts to summarize the state of the art of malaria vaccine development.

Some 50 phase I clinical trials of candidate vaccines against HIV/AIDS, 2 phase II trials and 2 phase III trials have been completed since the 1980s, altogether involving more than 16,000 volunteers. Although several neutralization epitopes have been identified on the surface of the virus glycoprotein spikes, the design of an envelope-based HIV vaccine capable of eliciting broadly reactive neutralizing antibodies remains as an elusive goal. A gp120- based vaccine, which was tested in two phase III trials, one in the USA and the other in Thailand, was found to be devoid of protective efficacy. The observation was made in the monkey model, using the simian immunodeficiency virus (SIV), that both virus loads and the clinical evolution of the disease were controlled by the CD8+ T-cell response (CTL) of the animals. This has prompted the development of vaccine candidates capable of inducing HIV-specific T-cell responses. A series of HIV vaccines based on live virus vectors already are in clinical studies, including a live recombinant canarypox virus vaccine (ALVAC), which is in phase III in Thailand, a non-replicative adenovirus type 5 (Ad5) vaccine, which has entered phase II clinical trials in the USA and The Caribbeans, and live recombinant vaccines based on the attenuated vaccinia virus MVA vector, which already have been through several phase I/II studies. These live recombinant vaccines have been evaluated either alone or as booster immunizations after priming with DNA vaccines. A whole array of other vaccines based on live vector vaccines, pseudoviral particles, peptides and other designs, have been tested in nonhuman primate models. So far, using the macaque/SIV model, none of the available vaccine candidates has been able to prevent infection following experimental challenge of the animals, but the vaccinated animals showed significant reduction of viral loads as compared to controls and were able to maintain their CD4+ T-cell count. T-cell stimulating vaccines thus illustrate a new paradigm in vaccinology, that of vaccines which are unable to prevent infection, but can prevent the occurrence of disease or at least slow down its evolution through continuous control of virus replication in the vaccinated host. The efficacy of these vaccines in humans now remains to be established.

This paper reviews the current status of research and development of vaccines against meningococcal disease due to Neisseria meningitidis, a major cause of severe meningitis and septicemia with epidemic potential. While five serogroups (A, B, C, Y, and W135) are responsible for most of the disease, Group A remains unique in its ability to cause large scale epidemics mainly in Africa but also in Asia. The majority of cases in Europe and America are due to Groups B and C. The successful experience with Hib and pneumococcal conjugate vaccines has paved the way for the development of polysaccharide conjugate vaccines for the prevention of meningococcal disease. Widespread vaccination with Group C conjugate vaccines now in use in several European countries indicates that these vaccines are immunogenic, induce immunological memory, reduce colonization and provide herd immunity to the general population. A monovalent group A conjugate vaccine being developed at an affordable price, offers hope for the elimination of large epidemics in African countries. Multivalent (A, C, Y, W) conjugate vaccines are being developed, and one has already been licensed. However, effective global prevention of meningococcal disease will not be achievable without the development of a vaccine against Group B meningitis, for which outer membrane protein vaccines are under development.

Since the discovery of AIDS in 1981, the global spread of HIV has reached pandemic proportions, representing a global developmental and public health threat. The development of a safe, globally effective and affordable HIV vaccine offers the best hope for the future control of the pandemic. Significant progress has been made over the past years in the areas of basic virology, immunology, pathogenesis of HIV/AIDS and the development of antiretroviral drugs. However, the development of an HIV vaccine faces formidable scientific challenges related to the high genetic variability of the virus, the lack of immune correlates of protection, limitations with the existing animal models and logistical problems associated with the conduct of multiple clinical trials. More than 35 vaccine candidates have been tested in Phase I/II clinical trials, involving more than 10,000 volunteers, and two Phase III trials have been completed, themselves involving more than 7500 volunteers. Multiple vaccine concepts and vaccination strategies have been tested, including DNA vaccines, subunit vaccines, live vectored recombinant vaccines and various prime-boost vaccine combinations. This article reviews the state of the art in HIV vaccine development, summarizes the results obtained so far and discusses the challenges to be met in the development of the various vaccine candidates.

Worldwide, enteric infections rank third among all causes of disease burden, being responsible for some 1.7-2.5 million deaths per year, mostly in young children and infants in developing countries. The main infectious agents responsible for human enteric infections include several viruses (enteric adenoviruses, astroviruses, human caliciviruses (HuCV), rotaviruses (RV)) and several bacterial agents, such as Campylobacter jejuni, a variety of pathogenic Escherichia coli strains including enterotoxigenic E. coli (ETEC), several Shigella species, various Salmonella strains including S. typhi and S. paratyphi, the agents of typhoid fever, and Vibrio cholerae, the agent of cholera. While effective vaccines are available at present against typhoid fever and cholera, no vaccine is available against illnesses caused by HuCV, Campylobacter, ETEC or the Shigellae. Rotavirus vaccines have had more success, although RV disease prevention suffered a major setback in 1999 with the withdrawal of a live simian-human reassortant RV vaccine less than a year after its introduction. New live oral RV vaccines have now been developed and are or should presently be ready for licensure. This article reviews the state of the art in vaccine R&D against human viral and bacterial enteric infections of public health importance.

One-fifth of global mortality, especially in children under the age of five is due to infectious diseases. Vaccines are effective at combating these diseases, as shown by the success of smallpox eradication, the impressive progress towards polio eradication, the significant achievements in measles mortality reduction and many others. New safe and effective vaccines must be developed for a variety of infections of public health importance against which no effective preventive intervention measure is either available or practical. In addition, appropriate mechanisms should be put in place to ensure access for all children to the needed vaccines. To meet these challenges, a new paradigm needs to be built among all stakeholders of immunization, including countries, industry, research institutions, foundations and international agencies like the World Health Organization (WHO) and the United Nations Children Fund (UNICEF). Importantly, developing countries should be empowered to participate actively in the development and introduction of new vaccines according to their national priorities.

Worldwide, acute respiratory infections (ARIs) constitute the leading cause of acute illnesses, being responsible for nearly 4 million deaths every year, mostly in young children and infants in developing countries. The main infectious agents responsible for ARIs include influenza virus, respiratory syncytial virus (RSV), parainfluenza virus type 3 (PIV-3), Streptococcus pneumoniae and Haemophilus influenzae. While effective vaccines against influenza, H. influenzae type b (Hib) and S. pneumoniae infections have been available for several years, no vaccine is available at present against illnesses caused by RSV, PIV-3, metapneumovirus or any of the three novel coronaviruses. In addition, the threat constituted by the multiple outbreaks of avian influenza during the last few years is urgently calling for the development of new influenza vaccines with broader spectrum of efficacy, which could provide immunity against an avian influenza virus pandemic. This article reviews the state of the art in vaccine R&D against ARIs and attempts to address these basic public health questions.

Substantial progress has been made during the past 15 years towards the development of improved vaccines for tuberculosis. This is due to advances in the characterization of genes and antigens of Mycobacterium tuberculosis (M. tb), aided by the availability of genome sequences of different mycobacterial species and M. tb isolates and to greater understanding of protective immune responses to the pathogen in both animals and humans. More than one hundred candidate vaccines have been tested in animal models, representing all of the major vaccine design strategies, and some have now moved into clinical trials. This review summarizes recent advances in tuberculosis vaccine development.

At least 49 phase I trials of candidate vaccines for HIV/AIDS, together with two phase II trials and two phase III trials have been completed since the mid 1980s, involving more than 35 different vaccine formulations, 14 different adjuvants and more than 12000 volunteers. Although several neutralizing epitopes have been identified on the surface of the virus glycoprotein spikes, the goal of an HIV envelope-based vaccine capable of eliciting broadly reactive neutralizing antibodies is elusive. A gp120-based vaccine, which was tested in two phase III trials (one in the USA and the other in Thailand), was found to have no protective efficacy when injected every 6 months. The observation that, in the monkey model, both viremia (virus load) and clinical outcome are controlled by the CD8+ T cell response, prompted the development of an array of candidate vaccines capable of inducing HIV-specific T cell responses. A series of HIV vaccines based on live virus vectors are already undergoing clinical studies, including a live recombinant canarypox virus vaccine (ALVAC), which is in phase III trials in Thailand, a non-replicative adenovirus type 5 (Ad5) vaccine, which is entering a phase II trial in the USA and the Caribbean, and live recombinant vaccines based on the attenuated vaccinia virus MVA vector, which have already completed several phase I studies, used either alone or combined with DNA vaccine priming. A whole array of other vaccines based on live vectors, DNA, peptides and other designs, are being tested in nonhuman primates. None of these vaccines has been able to prevent infection following experimental challenge, but all were found to control viral load and to prevent CD4 cell loss. T cell-stimulating vaccines are thus unable to prevent infection but prevent or slow disease progression by controlling virus replication. Their efficacy in humans remains to be determined.