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Objective To develop and evaluate a paper-based point-of-care HPV serology test to determine if an individual has received two or more HPV immunizations. Methods The paper-based immunoassay was constructed using a nitrocellulose lateral flow strip with adsorbed HPV16 virus-like particles serving as the capturing moiety. Three capture zones containing virus-like particles were placed in series to allow for visual discrimination between high and low HPV16 plasma antibody concentrations. A plasma separation membrane was used to allow whole blood to be applied directly to the assay. All reagents were dried on glass fiber pads during device fabrication and were rehydrated with buffer at the time of use. A pilot study consisting of 35 subjects with a history of zero, one, two or three HPV vaccines was conducted to evaluate the immunoassay. The completed paper-based immunoassays were scanned for visual interpretation by three researchers who were blinded to the true results and separately evaluated quantitatively using MATLAB. Results For the 28 tests valid for analysis, fifteen subjects reported receiving two or more HPV vaccines, three reported receiving one, and ten reported having no HPV vaccinations. The paper-based immunoassays for all fifteen subjects who reported having received two or more HPV vaccines were judged positive by all researchers. Twelve of the thirteen tests from individuals reporting one or zero vaccinations were deemed negative by all observers. One test from an unvaccinated individual was judged positive by two out of three reviewers. Quantitatively, all tests were correctly separated between the two groups. Conclusions We successfully designed and tested a HPV serology test amenable to the point-of-care. The device showed promising results in a pilot study for discriminating between those who received two or more HPV vaccinations and those who did not. Furthermore, this device offers a platform for producing other semi-quantitative point-of-care serological tests.

Most influenza vaccines are generally safe, but influenza vaccines can cause rare serious adverse events. Some adverse events, such as fever and febrile seizures, are more common in children than adults. There can be differences in the safety of vaccines in different populations due to underlying differences in genetic predisposition to the adverse event. Live attenuated vaccines have not been studied adequately in children under 2 years of age to determine the risks of adverse events; more studies are needed to address this and several other priority safety issues with all influenza vaccines in children. All vaccines intended for use in children require safety testing in the target age group, especially in young children. Safety of one influenza vaccine in children should not be extrapolated to assumed safety of all influenza vaccines in children. The low rates of adverse events from influenza vaccines should not be a deterrent to the use of influenza vaccines because of the overwhelming evidence of the burden of disease due to influenza in children.

This article presents the World Health Organization's (WHO) recommendations for the use of vaccines against diseases caused by human papillomaviruses (HPV) from the WHO position paper on Human papillomavirus vaccines: WHO position paper – October 2014, recently published in the Weekly Epidemiological Record [1]. This position paper summarizes the most recent developments in the field of HPV vaccines and the WHO position on HPV vaccine schedules in females. This document replaces the first WHO position paper on vaccines against diseases caused by HPV published in 2009 [2].Footnotes to this paper provide a number of core references. In accordance with its mandate to provide guidance to Member States on health policy matters, WHO issues a series of regularly updated position papers on vaccines and combinations of vaccines against diseases that have an international public health impact. These papers are concerned primarily with the use of vaccines in large-scale immunization programmes; they summarize essential background information on diseases and vaccines, and conclude with WHO's current position on the use of vaccines in the global context. This paper reflects the recommendations of WHO's Strategic Advisory Group of Experts (SAGE) on immunization. These recommendations were discussed by SAGE at its April 2014 meeting. Evidence presented at the meeting can be accessed at http://www.who.int/immunization/sage/previous/en/index.html.

This article presents the World Health Organizations (WHO) recommendations onthe use of hepatitis A vaccineexcerpted from the WHO position paper on hepatitis A vaccines – June 2012 recently published in the Weekly Epidemiological Record [1]. The current document replaces the position paper on the use of hepatitis A vaccines published in 2000 [2] and incorporates the most recent developments in the field with particular consideration to changes in the epidemiological features of hepatitis A infection in several countries, increased supply of hepatitis A vaccines, and new evidence on their public health benefits.Footnotes to this paper provide a number of core references including references to grading tables that assess the quality of scientific evidence for a few key conclusions.In accordance with its mandate to provide guidance to Member States on health policy matters, WHO issues a series of regularly updated positionpapers on vaccines and combinations of vaccines against diseases that have an international public health impact. These papers are concerned primarily with the use of vaccines in large-scale immunization programmes; they summarize essential background information on diseases and vaccines, and conclude with WHO's current position on the use of vaccines in the global context. This paper reflects the recommendations of WHO's Strategic Advisory Group of Experts (SAGE) on immunization. These recommendations were discussed by SAGE at its November 2011 and April 2012 meetings. Evidence presented at these meetings can be accessed at http://www.who.int/immunization/sage/previous/en/index.html.

The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) was formed to evaluate the safety and characteristics of live, recombinant viral vector vaccines. The Modified Vaccinia Ankara (MVA) vector system is being explored as a platform for development of multiple vaccines. This paper reviews the molecular and biological features specifically of the MVA-BN vector system, followed by a template with details on the safety and characteristics of an MVA-BN based vaccine against Zaire ebolavirus and other filovirus strains. The MVA-BN-Filo vaccine is based on a live, highly attenuated poxviral vector incapable of replicating in human cells and encodes glycoproteins of Ebola virus Zaire, Sudan virus and Marburg virus and the nucleoprotein of the Thai Forest virus. This vaccine has been approved in the European Union in July 2020 as part of a heterologous Ebola vaccination regimen. The MVA-BN vector is attenuated following over 500 serial passages in eggs, showing restricted host tropism and incompetence to replicate in human cells. MVA has six major deletions and other mutations of genes outside these deletions, which all contribute to the replication deficiency in human and other mammalian cells. Attenuation of MVA-BN was demonstrated by safe administration in immunocompromised mice and non-human primates. In multiple clinical trials with the MVA-BN backbone, more than 7800 participants have been vaccinated, demonstrating a safety profile consistent with other licensed, modern vaccines. MVA-BN has been approved as smallpox vaccine in Europe and Canada in 2013, and as smallpox and monkeypox vaccine in the US in 2019. No signal for inflammatory cardiac disorders was identified throughout the MVA-BN development program. This is in sharp contrast to the older, replicating vaccinia smallpox vaccines, which have a known risk for myocarditis and/or pericarditis in up to 1 in 200 vaccinees. MVA-BN-Filo as part of a heterologous Ebola vaccination regimen (Ad26.ZEBOV/MVA-BN-Filo) has undergone clinical testing including Phase III in West Africa and is currently in use in large scale vaccination studies in Central African countries. This paper provides a comprehensive picture of the MVA-BN vector, which has reached regulatory approvals, both as MVA-BN backbone for smallpox/monkeypox, as well as for the MVA-BN-Filo construct as part of an Ebola vaccination regimen, and therefore aims to provide solutions to prevent disease from high-consequence human pathogens.

The authors of Huijbers et al. [1] apologize for not giving sufficient credit to the work presented by Saupe et al. [2], Huijbers et al. [3] and Femel et al. [4]. Below are corrections to the relevant parts of the article. The authors would like to apologize for any inconvenience caused. Page 3054 (Introduction) The sentence: ‘In previous work we have shown that it is possible to break self-tolerance in mice, and to induce antibody responses against the tumor vascular markers extra domain A (EDA) and B (EDB) of the extracellular matrix molecule fibronectin.’, should be replaced by: ‘Previous work of Huijbers et al. [3] and Femel et al. [4] has shown that it is possible to break self-tolerance in mice, and to induce antibody responses against the tumor vascular markers extra domain A (EDA) and B (EDB) of the extracellular matrix molecule fibronectin.’ Page 3056 (Discussion) The sentence: ‘We have previously shown that the anti-self antibody response against EDB is decreased as the amount of TRX is increased.’, should be replaced by: ‘Saupe et al. [2] have previously shown that the anti-self antibody response against EDB is decreased as the amount of TRX is increased.’ Page 3057 (Discussion) The sentence: ‘In this paper we show that the TRX-part is absolutely required to induce an immune response against EDB and that vaccination with EDB alone does not induce an antibody response against EDB.’, should be replaced by: ‘In this paper Saupe et al. [2] show that the TRX-part is absolutely required to induce an immune response against EDB and that vaccination with EDB alone does not induce an antibody response against EDB.’ Page 3058 (Discussion) The sentence: ‘To address this issue, we have previously used the MMTV-PyMT transgenic model of breast cancer. Since EDB is not expressed in this model we approached the question with a vaccine against the extra domain A of fibronectin (EDA).’, should be replaced by: ‘This issue was previously addressed by Femel et al. [4] using the MMTV-PyMT transgenic model of breast cancer. Since EDB is not expressed in this model the question was approached with a vaccine against the extra domain A of fibronectin (EDA).’ The sentence: ‘We have looked into more detail at the immune response induced with the TRX-EDB vaccine [12] and found that the major subclass induced by the vaccine was IgG1, which is characteristic of a Th2-response, thus an antibody mediated immune response in mice. Furthermore, we found macrophages trying to engulf the tumor vessels in the tumors of mice vaccinated with TRX-EDB, increased fibrinogen leakage and increased neutrophil infiltration in these tumors.’, should be replaced by: ‘Huijbers et al. [3] have looked into more detail at the immune response induced with the TRX-EDB vaccine and found that the major subclass induced by the vaccine was IgG1, which is characteristic of a Th2-response, thus an antibody mediated immune response in mice. Furthermore, they found macrophages trying to engulf the tumor vessels in the tumors of mice vaccinated with TRX-EDB, increased fibrinogen leakage and increased neutrophil infiltration in these tumors.’ After the sentence: ‘The current study demonstrates that several alternative non-self fusion partners in conjugate vaccines can elicit strong and specific antibody responses against self-antigens.’, this sentence should be added: ‘This was also observed in a study by Saupe et al. in which VLRB (variable lymphocyte receptor B) conjugate vaccines were used [2]. This study concluded that the foreign antigen should be short (around 41 aa in size), have multimerizing capacity to provide a strong B cell activation signal and be hidden inside the vaccine protein to avoid epitope masking or clearance of the fusion protein.’ Page 3058 (Experimental procedures) The sentence: ‘The pET21-TRX vector was a kind gift of Dr. Anna-Karin Olsson (Uppsala University, Uppsala, Sweden).’, should be replaced by: ‘Both the pET21-TRX vector and the pET21a-TRX-EDB vector were a kind gift of Dr. Anna-Karin Olsson (Uppsala University, Uppsala, Sweden).’

Background Within-host models describe the dynamics of immune cells when encountering a pathogen, and how these dynamics can lead to an individual-specific immune response. This systematic review aims to summarize which within-host methodology has been used to study and quantify antibody kinetics after infection or vaccination. In particular, we focus on data-driven and theory-driven mechanistic models. Materials PubMed and Web of Science databases were used to identify eligible papers published until May 2022. Eligible publications included those studying mathematical models that measure antibody kinetics as the primary outcome (ranging from phenomenological to mechanistic models). Results We identified 78 eligible publications, of which 8 relied on an Ordinary Differential Equations (ODEs)-based modelling approach to describe antibody kinetics after vaccination, and 12 studies used such models in the context of humoral immunity induced by natural infection. Mechanistic modeling studies were summarized in terms of type of study, sample size, measurements collected, antibody half-life, compartments and parameters included, inferential or analytical method, and model selection. Conclusions Despite the importance of investigating antibody kinetics and underlying mechanisms of (waning of) the humoral immunity, few publications explicitly account for this in a mathematical model. In particular, most research focuses on phenomenological rather than mechanistic models. The limited information on the age groups or other risk factors that might impact antibody kinetics, as well as a lack of experimental or observational data remain important concerns regarding the interpretation of mathematical modeling results. We reviewed the similarities between the kinetics following vaccination and infection, emphasising that it may be worth translating some features from one setting to another. However, we also stress that some biological mechanisms need to be distinguished. We found that data-driven mechanistic models tend to be more simplistic, and theory-driven approaches lack representative data to validate model results.

Sustainable demand for seasonal influenza vaccines is a component of national security strategies for pandemic preparedness. However, the ongoing COVID-19 pandemic has revealed many weaknesses in the capacity of countries to design and execute sustainable vaccination programs. An influenza pandemic remains a global threat and yet there is no global monitoring system for assessing progress towards influenza vaccination coverage targets. The International Federation of Pharmaceutical Manufacturers and Associations' (IFPMA) Influenza Vaccine Supply International Task Force (IVS) developed a survey method in 2008 to estimate seasonal influenza vaccination coverage rates, which in turn serves as a crude estimate of pandemic preparedness. It provides evidence to guide expanded efforts for pandemic preparedness, specifically for increasing COVID-19 vaccine immunization levels. Furthermore, the results presented herein serve as a proxy for assessing the state of pandemic preparedness at a global and regional level. This paper adds data from 2018 and 2019 to the previous analyses. The current data show an upward or stable global trend in seasonal influenza vaccine dose distributed per 1,000 population with a 7% increase between 2017 and 2018 and 6% increase between 2018 and 2019. However, considerable regional inequities in access to vaccine persist. Three regions, Africa, the Middle-east, and Southeast Asia together account for 50% of the global population but only 6% of distributed seasonal influenza vaccine doses. This is an important finding in the context of the ongoing COVID-19 pandemic, as distribution of influenza vaccine doses in many ways reflects access to COVID-19 vaccines. Moreover, improving seasonal vaccine uptake rates is critical for optimizing the annual benefits by reducing the huge annual influenza-associated societal burdens and by providing protection to vulnerable individuals against serious complications from seasonal influenza infections.

Highlights • Dynamic transmission models of infectious disease capture the herd immunity effects of vaccination. • We compared dynamic and static models of maternal acellular pertussis (aP) immunization built with Brazilian data. • At infant vaccine coverage 90–95%. • The background effect of routine infant vaccination is critical to the cost-effectiveness of maternal aP immunization., Background This paper compares cost-effectiveness results from two models of maternal immunization to prevent pertussis in infants in Brazil, one static, one dynamic, to explore when static models are adequate for public health decisions and when the extra effort required by dynamic models is worthwhile. Methods We defined two scenarios to explore key differences between static and dynamic models, herd immunity and time horizon. Scenario 1 evaluates the incremental cost/DALY of maternal acellular pertussis (aP) immunization as routine infant vaccination coverage ranges from low/moderate up to, and above, the threshold at which herd immunity begins to eliminate pertussis. Scenario 2 compares cost-effectiveness estimates over the models’ different time horizons. Maternal vaccine prices of $9.55/dose (base case) and $1/dose were evaluated. Results The dynamic model shows that maternal immunization could be cost-saving as well as life-saving at low levels of infant vaccination coverage. When infant coverage reaches the threshold range (90–95%), it is expensive: the dynamic model estimates that maternal immunization costs $2 million/DALY at infant coverage > 95% and maternal vaccine price of $9.55/dose; at $1/dose, cost/DALY is $200,000. By contrast, the static model estimates costs/DALY only modestly higher at high than at low infant coverage. When the models’ estimates over their different time horizons are compared at infant coverage

Antibiotic resistance is increasing and one strategy to prevent resistance development is the use of bacterial vaccines. For Gram-negative bacteria, natural outer membrane vesicles (OMVs) could be used for vaccine development. These vesicular structures are naturally produced by all Gram-negative bacteria and contain several antigens in their native environment. However, despite that the presence of lipopolysaccharide (LPS) may aid as intrinsic adjuvant, there is a risk that it may also cause undesired immune responses. Therefore, molecules to dampen LPS-induced toll-like receptor (TLR) 4 activation may be needed. Here host defense peptides (HDPs), like cathelicidins, can play an important role. They have been shown to interact with LPS and thereby neutralize LPS-induced TLR4 activation. However, there is currently no knowledge about neutralization in an OMV-based setting. Therefore, in this paper the immune modulating capacity of HDPs was investigated after macrophage stimulation with either spontaneous or heat-induced B. bronchiseptica OMVs. This revealed that the cathelicidins LL-37, CATH-2, PMAP-36 and K9CATH were able to modulate immune responses. Interestingly, immune modulation by these cathelicidins was different for spontaneous compared to heat-induced OMVs. Interaction studies revealed that the mode of binding of cathelicidins to OMVs slightly differed between OMV classes. Furthermore, TLR screening revealed that TLR2, 4, 5 and 9 were involved in stimulation of macrophages by OMVs, with TLR4-mediated activation being the most important pathway. Uptake of OMVs did not play a major role in macrophage activation. Taken together, this study shows how OMVs can activate macrophages and how cathelicidins may modulate these immune responses.

Dear Editor, in their article, Garcia and Cerda [1] found a relatively high vaccine acceptance rate (90 6%) and stated that the COVID-19 pandemic has not only had a negative impact on people’s health and life behavior, but also on economies around the world Chi-squared and z-tests showed that the percentage of willing people is significantly higher amongst those who agree with the statement “I have the primary responsibility for preventing the infection by COVID-19” (63%) when compared with those who disagree (42 6%) [ ]our data showed that the percentage is higher amongst those people who agree that preventive behaviours are an act of social responsibility (64 1%), when compared to those who don’t agree (24 9%) In our opinion, developing a COVID-19 public vaccination program should start from considering people’s attitudes to engage them in an educational campaign focused on fostering the citizens-science alliance 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

Launched at Davos in January 2017 with funding from sovereign investors and philanthropic institutions, the Coalition for Epidemic Preparedness Innovations (CEPI) is an innovative partnership between public, private, philanthropic, and civil organisations whose mission is to stimulate, finance and co-ordinate vaccine development against diseases with epidemic potential in cases where market incentives fail. As of December 2019, CEPI has committed to investing up to $706 million in vaccine development. This includes 19 vaccine candidates against its priority pathogens (Lassa fever virus, Middle East respiratory syndrome coronavirus, Nipah virus, Chikungunya, Rift Valley fever) and three vaccine platforms to develop vaccines against Disease X, a novel or unanticipated pathogen. As an entity largely supported by public funds, ensuring equitable access to vaccines whose development it supports in low- and middle-income countries is CEPI's primary focus. CEPI developed an initial equitable access policy shortly after its formation, with key stakeholders expressing strong views about its content and prescriptive nature. The CEPI board instructed that it be revisited after a year. This paper describes the process of revising the policy, and how key issues were resolved. CEPI will continue to take an iterative, rather than prescriptive, approach to its policy-one that reflects the needs of multiple stakeholders and ensures it can meet its equitable access goals.

Highlights • Efficient laboratories are key to the success of any disease programme. • PEI resources have contributed efforts in strengthening laboratory capacity in the region. • These contributions have not been systematically documented as lesson learnt. • With PEI programme on the ramp down, this paper documents it contributions for posterity., Background The laboratory has always played a very critical role in diagnosis of the diseases. The success of any disease programme is based on a functional laboratory network. Health laboratory services are an integral component of the health system. Efficiency and effectiveness of both clinical and public health functions including surveillance, diagnosis, prevention, treatment, research and health promotion are influenced by reliable laboratory services. The establishment of the African Regional polio laboratory for the Polio Eradication Initiative (PEI) has contributed in supporting countries in their efforts to strengthen laboratory capacity. On the eve of the closing of the program, we have shown through this article, examples of this contribution in two countries of the African region: Côte d’Ivoire and the Democratic Republic of Congo. Methods Descriptive studies were carried out in Côte d’Ivoire (RCI) and Democratic Republic of Congo (DRC) from October to December 2014. Questionnaires and self-administered and in-depth interviews and group discussions as well as records and observation were used to collect information during laboratory visits and assessments. Results The PEI financial support allows to maintain the majority of the 14 (DRC) and 12 (RCI) staff involved in the polio laboratory as full or in part time members. Through laboratory technical staff training supported by the PEI, skills and knowledge were gained to reinforce laboratories capacity and performance in quality laboratory functioning, processes and techniques such as cell culture. In the same way, infrastructure was improved and equipment provided. General laboratory quality standards, including the entire laboratory key elements was improved through the PEI accreditation process. Conclusion The Polio Eradication Initiative (PEI) is a good example of contribution in strengthening public health laboratories systems in the African region. It has established strong Polio Laboratory network that contributed to the strengthening of capacities and its expansion to surveillance of other viral priority diseases such as measles, yellow fever, Influenza, MERS-CoV and Ebola. This could serve as lesson and good example of laboratory based surveillance to improving diseases prevention, detection and control in our middle and low income countries as WHO and partners are heading to polio eradication in the world.

Efficacy trials of preventive hepatitis C virus (HCV) vaccine candidates raise challenging scientific and ethical issues. Based on data from the first 3 years of a community-based prospective observational study – the Hepatitis C Incidence and Transmission Study-community (HITS-c) – this paper examines the feasibility of conducting trials of candidate HCV vaccines with people who inject drugs (PWID) in Sydney, Australia. Of the 166 PWID confirmed HCV antibody negative and eligible for enrolment, 156 (94%) completed baseline procedures. Retention was high, with 89% of participants retained at 48 weeks and 76% of participants completing at least 75% of study visits within 2 weeks of schedule. The rate of primary HCV infection was 7.9/100 py (95% CI 4.9, 12.7). Of the 17 incident cases, 16 completed at least one follow-up assessment and 12 (75%) had evidence of chronic viraemia with progression to chronic HCV infection estimated to be 6/100 py. Power calculations suggest a chronic HCV infection rate of at least 12/100 py (primary HCV infection rate 16/100 py) will be required for stand-alone trials of highly efficacious candidates designed to prevent chronic infection. However, elevated primary HCV infection was observed among participants not receiving opioid substitution therapy who reported heroin as the main drug injected (26.9/100 py, 95% CI 14.5, 50.0) and those who reported unstable housing (23.5/100 py, 95% CI 7.6, 72.8), daily or more frequent injecting (22.7/100 py, 95% CI 12.2, 42.2) and receptive syringe sharing (23.6/100 py, 95% CI 9.8, 56.7) in the 6 months prior to baseline. These data suggest that it is possible to recruit and retain at-risk PWID who adhere to study protocols and that modification of eligibility criteria may identify populations with sufficiently high HCV incidence. Results support the feasibility of large multi-centre HCV vaccine trials, including in the Australian setting.

The resurgence of pertussis suggests the need for greater efforts in understanding the long-lasting protective responses induced by vaccination. In this paper we dissect the persistence of humoral and B-cell memory responses induced by primary vaccination with two different acellular pertussis (aP) vaccines, hexavalent Hexavac(®) vaccine (Hexavac) (Sanofi Pasteur MSD) and Infanrix hexa(®) (Infanrix) (GlaxoSmithKline Biologicals). We evaluated the specific immune responses in the two groups of children, 5 years after primary vaccination by measuring the persistence of IgG and antibody secreting cells (ASC) specific for vaccine antigens. Part of the enrolled children received only primary vaccination, while others had the pre-school boost dose. A similar level of antigen-specific IgG and ASC was found in Infanrix and Hexavac vaccinated children. The mean IgG levels were significantly higher in children that received the pre-school boost as compared with children that did not receive the boost dose. A longer persistence after the pre-school boost of IgG-Pertussis Toxin (PT) and IgG-pertactin levels was observed in Infanrix primed children, but it was not statistically significant. More than 80% of children presented a positive ASC B memory response. Around 50% of children still presented protective IgG-PT levels which are reduced to 36% in no-boosted children. The pre-school booster dose restores the percentage of protected children above 50%. In conclusion our data underline the importance of giving a booster dose 5 years after primary vaccination and suggest the need for a new vaccine able to induce a long lasting protective response.

Infection with human influenza virus leads to serious respiratory disease. Vaccination is the most common and effective prophylactic measure to prevent influenza. Influenza vaccine manufacturing and release is controlled by the correct determination of the potency-defining haemagglutinin (HA) content. This determination is historically done by single radial immunodiffusion (SRID), which utilizes a statistical slope-ratio model to estimate the actual HA content. In this paper we describe the development and qualification of a parallel line model for analysis of HA quantification by SRID in cell culture-derived whole virus final monovalent and trivalent influenza vaccines. We evaluated plate layout, sample randomization, and validity of data and statistical model. The parallel line model was shown to be robust and reproducible. The precision studies for HA content demonstrated 3.8-5.0% repeatability and 3.8%-7.9% intermediate precision. Furthermore, system suitability criteria were developed to guarantee long-term stability of this assay in a regulated production environment. SRID is fraught with methodological and logistical difficulties and the determination of the HA content requires the acceptance of new and modern release assays, but until that moment, the described parallel line model represents a significant and robust update for the current global influenza vaccine release assay. (C) 2011 Elsevier Ltd. All rights reserved.

Highlights ► BEVS has matured into a commercial manufacturing technology. ► A broad range of vaccines can be produced in a universal “plug and play” process. ► Vaccines can be produced at affordable prices. ► BEVS can offer sustainability of vaccine supply., The baculovirus-insect cell expression system is a well known tool for the production of complex proteins. The technology is also used for commercial manufacture of various veterinary and human vaccines. This review paper provides an overview of how this technology can be applied to produce a multitude of vaccine candidates. The key advantage of this recombinant protein manufacturing platform is that a universal “plug and play” process may be used for producing a broad range of protein-based prophylactic and therapeutic vaccines for both human and veterinary use while offering the potential for low manufacturing costs. Large scale mammalian cell culture facilities previously established for the manufacturing of monoclonal antibodies that have now become obsolete due to yield improvement could be deployed for the manufacturing of these vaccines. Alternatively, manufacturing capacity could be established in geographic regions that do not have any vaccine production capability. Dependent on health care priorities, different vaccines could be manufactured while maintaining the ability to rapidly convert to producing pandemic influenza vaccine when the need arises.

This paper describes a proposed Strategic Vaccine Facility (SVF) to provide a capability to the UK to deal with new and emerging disease threats. It would underpin the vaccine manufacturing industry by developing expertise and technology to enable rapid manufacture of small batches of vaccines for emergency use against agents, such as bioterrorist agents and emerging diseases. It would have a rare ability to work with dangerous pathogens under containment, allowing the production of inactivated and live vaccines, which would be difficult in a conventional plant. The facility's output will include vaccine candidates and manufacturing protocols for transfer to industry, small vaccine batches for emergency use or clinical trials, and vaccine reference standards. It would also be available for manufacturing small batches of experimental and public health vaccines for the UK and the developing world, allowing clinical trials to be undertaken against key diseases.

Dengue is a rapidly growing public health threat with approximately 2.5billion people estimated to be at risk. Several vaccine candidates are at various stages of pre-clinical and clinical development. Thus far, live dengue vaccine candidates have been administered to several thousands of volunteers and were well-tolerated, with minimal short-term safety effects reported in Phase I and Phase II clinical trials. Based on the natural history of dengue, a theoretical possibility of an increased risk of severe dengue as a consequence of vaccination has been hypothesized but not yet observed. In October 2011, the World Health Organization (WHO) convened a consultation of experts in dengue, vaccine regulation and vaccine safety to review the current scientific evidence regarding safety concerns associated with live attenuated dengue vaccines and, in particular, to consider methodological approaches for their long-term evaluation. In this paper we summarize the scientific background and methodological considerations relevant to the safety assessment of these vaccines. Careful planning and a coordinated approach to safety assessment are recommended to ensure adequate long-term evaluation of dengue vaccines that will support their introduction and continued use.

The relationship between influenza antigenic drift and vaccination lies at the intersection of evolutionary biology and public health, and it must be viewed and analyzed in both contexts simultaneously. In this paper, I review what is known about the effects of antigenic drift on vaccination and the effects of vaccination on antigenic drift, and I suggest some simple ways to detect the presence of antigenic drift in seasonal influenza data. If antigenic drift occurs on the time scale of a single influenza season, it may be associated with the presence of herd immunity at the beginning of the season and may indicate a need to monitor for vaccine updates at the end of the season. The relationship between antigenic drift and vaccination must also be viewed in the context of the global circulation of influenza strains and the seeding of local and regional epidemics. In the data sets I consider — from New Zealand, New York, and France — antigenic drift can be statistically detected during some seasons, and seeding of epidemics appears to be endogenous sometimes and exogenous at other times. Improved detection of short-term antigenic drift and epidemic seeding would significantly benefit influenza monitoring efforts and vaccine selection.

Influenza causes substantial mortality in high-risk groups despite targeted vaccination programmes. This paper considers whether it is worth vaccinating healthcare workers (HCWs) against influenza to protect high-risk patients in a series of systematic reviews and an economic evaluation. Eighteen studies are included. Vaccination was highly effective in HCWs, with minimal adverse effects. Two trials assessed patient mortality after vaccinating HCWs, both of which showed a reduction. Despite recommendations, less than 25% of HCW in Europe and the UK are vaccinated. Five studies looked at programmes to increase uptake; these produced increases of 5%-45%. Published economic evaluations did not include patient benefit; therefore, an economic evaluation using UK data was undertaken. In the base case, vaccination was cost saving (pounds 12/vaccinee). In the most pessimistic scenario it cost pounds 405/life-year gained. Effective implementation should be a priority.

The European Commission (EC) has strong commitments and recognises the need to continue to ensure that HIV/AIDS research efforts receive global attention. The EC is facing this challenge in a global context and has made substantial investments together with European Developing Countries Clinical Trial Partnership (EDCTP) to formulate a program for the accomplishment of a scientific strategic plan promoting the European/African HIV vaccine development approach. The EC and EDCTP has convened a number of meetings by experts in basic and clinical virology, immunology, epidemiology, as well as industrial and regulatory representatives. The remit of the committee of experts was to define (1) objective criteria for selection of HIV candidates; (2) to determine criteria for selection of sites for clinical trials in Europe and Africa. The resulting consensus paper will guide the EC and EDCTP in developing HIV vaccine strategy and recommendations.

Vaccines are among the most cost-effective interventions against infectious diseases. Many candidate vaccines targeting neglected diseases in low- and middle-income countries are now progressing to large-scale clinical testing. However, controversy surrounds the appropriate design of vaccine trials and, in particular, the use of unvaccinated controls (with or without placebo) when an efficacious vaccine already exists. This paper specifies four situations in which placebo use may be acceptable, provided that the study question cannot be answered in an active-controlled trial design; the risks of delaying or foregoing an efficacious vaccine are mitigated; the risks of using a placebo control are justified by the social and public health value of the research; and the research is responsive to local health needs. The four situations are: (1) developing a locally affordable vaccine, (2) evaluating the local safety and efficacy of an existing vaccine, (3) testing a new vaccine when an existing vaccine is considered inappropriate for local use (e.g. based on epidemiologic or demographic factors), and (4) determining the local burden of disease.

This paper provides an examination of the ethics of disease eradication policies. It examines three arguments that have been advanced for thinking that eradication is in some way ethically exceptional as a policy goal. These are (1) global eradication has symbolic importance, (2) disease eradication is a global public good and (3) disease eradication is a form of rescue. It argues that none of these provides a good reason to think that individuals have special duties to facilitate eradication campaigns, or that public health authorities have special permissions to pursue them. But the fact that these arguments fail does not entail that global disease eradication is ethically problematic, or that it should not be undertaken. Global eradication of a disease, if successful, is a way of providing an enormous health benefit that stretches far into the future. There is no need to reach for the idea that there is a special duty to eradicate disease; the same considerations that are in play in ordinary public health policy – of reducing the burden of disease equitably and efficiently – suffice to make global disease eradication a compelling goal where doing so is feasible.

Recombinant subunit vaccines in general are poor immunogens likely due to the small size of peptides and proteins, combined with the lack or reduced presentation of repetitive motifs and missing complementary signal(s) for optimal triggering of the immune response. Therefore, recombinant subunit vaccines require enhancement by vaccine delivery vehicles in order to attain adequate protective immunity. Particle-based delivery platforms, including particulate antigens and particulate adjuvants, are promising delivery vehicles for modifying the way in which immunogens are presented to both the innate and adaptive immune systems. These particle delivery platforms can also co-deliver non-specific immunostimodulators as additional adjuvants. This paper reviews efforts and advances of the Particle-based delivery platforms in development of vaccines against malaria, a disease that claims over 600,000 lives per year, most of them are children under 5 years of age in sub-Sahara Africa.

The rapid development of purification processes for polysaccharide vaccines is constrained by a lack of analytical tools current technologies for the measurement of polysaccharide recovery and process-related impurity clearance are complex, time-consuming, and generally not amenable to high throughput process development (HTPD). HTPD is envisioned to be central to the improvement of existing polysaccharide manufacturing processes through the identification of critical process parameters that potentially impact the quality attributes of the vaccine and to the development of de novo processes for clinical candidates, across the spectrum of downstream processing. The availability of a fast and automated analytics platform will expand the scope, robustness, and evolution of Design of Experiment (DOE) studies.This paper details recent advances in improving the speed, throughput, and success of in-process analytics at the micro-scale. Two methods, based on modifications of existing procedures, are described for the rapid measurement of polysaccharide titre in microplates without the need for heating steps. A simplification of a commercial endotoxin assay is also described that features a single measurement at room temperature. These assays, along with existing assays for protein and nucleic acids are qualified for deployment in the high throughput screening of polysaccharide feedstreams. Assay accuracy, precision, robustness, interference, and ease of use are assessed and described. In combination, these assays are capable of measuring the product concentration and impurity profile of a microplate of 96 samples in less than one day. This body of work relies on the evaluation of a combination of commercially available and clinically relevant polysaccharides to ensure maximum versatility and reactivity of the final assay suite. Together, these advancements reduce overall process time by up to 30-fold and significantly reduce sample volume over current practices. The assays help build an analytical foundation to support the advent of HTPD technology for polysaccharide vaccines. It is envisaged that this will lead to an expanded use of Quality by Design (QbD) studies in vaccine process development.

The modified vaccinia virus Ankara (MVA) strain is a highly attenuated strain of vaccinia virus that has been demonstrated to be safe for humans. MVA is widely considered as the vaccinia virus strain of choice for clinical investigation because of its high safety profile. It also represents an excellent candidate for use as vector system in recombinant vaccine development for gene delivery or vaccination against infectious diseases or tumours, even in immunocompromised individuals. The use of MVA and recombinant MVA vectors must comply with various regulatory requirements, particularly relating to the assessment of potential risks for human health and the environment. The purpose of the present paper is to highlight some biological characteristics of MVA and MVA-based recombinant vectors and to discuss these from a biosafety point of view in the context of the European regulatory framework for genetically modified organisms with emphasis on the assessment of potential risks associated with environmental release.