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Introduction: Coronavirus Disease 2019 (COVID-19) poses a substantial threat to the lives of the elderly, especially those with neurodegenerative diseases, and vaccination against viral infections is recognized as an effective measure to reduce mortality. However, elderly patients with neurodegenerative diseases often suffer from abnormal immune function and take multiple medications, which may complicate the role of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines. Currently, there is no expert consensus on whether SARS-CoV-2 vaccines are suitable for patients with neurodegenerative diseases., Areas Covered: We searched Pubmed to conduct a systematic review of published studies, case reports, reviews, meta-analyses, and expert guidelines on the impact of SARS-CoV-2 on neurodegenerative diseases and the latest developments in COVID-19 vaccines. We also summarized the interaction between vaccines and age-related neurodegenerative diseases. The compatibility of future SARS-CoV-2 vaccines with neurodegenerative diseases is discussed., Expert Opinion: Vaccines enable the body to produce immunity by activating the body's immune response. The pathogenesis and treatment of neurodegenerative diseases is complex, and these diseases often involve abnormal immune function, which can substantially affect the safety and effectiveness of vaccines. In short, this article provides recommendations for the use of vaccine candidates in patients with neurodegenerative diseases.

Introduction : Children with autoimmune diseases often require treatment with systemic immunosuppressives. Efficacy and safety of vaccination, particularly live-attenuated viral vaccines in these patients remain a concern. Areas covered : To evaluate the immunogenicity and safety of viral vaccines in children and young people treated with systemic immunosuppressive drugs for autoimmune diseases. A systemic literature review was performed using Pubmed including English papers in subjects less than 21 years old. Viral vaccines were generally immunogenic and safe in children receiving immunosuppressive drugs, including biologics. Use of low-dose prednisolone or disease-modifying antirheumatic drugs did not significantly impact on vaccine immunogenicity, although there was anecdotal evidence of reduced immunogenicity in patients receiving high-dose prednisolone/methylprednisolone and pulse cyclophosphamide. Patients on biologics mounted adequate seroprotective responses, but antibody titers tended to be lower. Both live-attenuated and inactivated vaccines were well tolerated with no serious adverse events. Autoimmune disease activity was not adversely affected by vaccination. Expert opinion : Current evidence indicates that administration of viral vaccines to children with autoimmune diseases receiving most systemic immunosuppressive drugs is immunogenic and safe. MMR can safely be given to most patients receiving biologics, but patients on high-dose prednisolone and pulse cyclophosphamide should avoid MMR and other live viral vaccines.

Introduction: Preterm infants (PIs) are at increased risk of vaccine-preventable diseases (VPDs). However, delayed vaccination start and low vaccine coverage are still reported. Areas covered: This systematic review includes 37 articles on preterm vaccination published in 2008-2018 in PubMed. Both live attenuated and inactivated vaccines are safe and well tolerated in PIs. Local reactions, apnea, and reactivity changes are the most frequently reported adverse events. Lower gestational age and birth weight, preimmunization apnea, longer use of continuous positive airway pressure (CPAP) are risk factors for apnea. The proportion of PIs who develop protective humoral and cellular immunity is generally similar to full terms although later gestational age is associated with increased antibody IgG concentrations (i.e. against certain pneumococcal serotypes, influenza, hepatitis B virus and poliovirus 1) and increased mononuclear cells proliferation (i.e. after inactivated poliovirus). Expert opinion: PIs can be safely and adequately protected by available vaccines with the same schedule used for full terms. Data at this regard have been retrieved by studies using a 3-dose primary series for pneumococcal and hexavalent vaccines. Further studies are needed regarding the 2 + 1 schedule. Apnea represents a nonspecific stress response in PIs, thus those hospitalized at 2 months should have cardio-respiratory monitoring after their first vaccination.

Introduction: Adjuvants form an integral component in most of the inactivated and subunit vaccine formulations. Careful and proper selection of adjuvants helps in promoting appropriate immune responses against target pathogens at both innate and adaptive levels such that protective immunity can be elicited. Areas covered: Herein, we describe the recent progress in our understanding of the mode of action of adjuvants that are licensed for use in human vaccines or in clinical or pre-clinical stages at both innate and adaptive levels. Different pathogens have distinct characteristics, which require the host to mount an appropriate immune response against them. Adjuvants can be selected to elicit a tailor-made immune response to specific pathogens based on their unique properties. Identification of biomarkers of adjuvanticity for several candidate vaccines using omics-based technologies can unravel the mechanism of action of modern and experimental adjuvants. Expert opinion: Adjuvant technology has been revolutionized over the last two decades. In-depth understanding of the role of adjuvants in activating the innate immune system, combined with systems vaccinology approaches, have led to the development of next-generation, novel adjuvants that can be used in vaccines against challenging pathogens and in specific target populations.

Introduction: One of the essential mechanisms of virus infection control is cell-mediated cytotoxicity, which can act in an antibody-dependent or -independent fashion and is provided by different effector cells. The role of CD8 T-cells in infection control and in affecting the pathological outcome of different types of infection has been demonstrated in numerous animal studies. Despite this, their role in controlling human influenza infection is not fully understood. Especially, knowledge about their induction and turnover in human influenza infection is limited. Differences in the development of CD8 T-cells after influenza infection or immunizations should be explored in detail, in relation to the bioaccessibility of influenza antigens, site of application and distribution routes., Areas Covered: This review focuses on the basics of CD8 T-cell immune response both in human influenza infection and after administration of inactivated or live attenuated influenza vaccine. Some aspects of the accessibility, distribution and presentation of influenza antigens to CD8 T-cells are described., Expert Commentary: The CD8 T-cell response is an essential connection between innate and antibody-mediated responses, which are all-important for influenza control. We hypothesize that immunization with live influenza vaccine is the most straightforward artificial way to induce an efficient influenza-specific CD8 T-cell response.

Introduction: Hand, foot, and mouth disease (HFMD) is a childhood illness commonly caused by enterovirus A. Enterovirus A71 (EV-A71) and coxsackievirus A16 (CV-A16) are the most commonly identified viruses associated with HFMD. Recently, outbreaks caused by different enterovirus A including CV-A6 and CV-A10 are increasing. Being available now to protect against EV-A71 infection, inactivated EV-A71 vaccines cannot prevent coxsackievirus infections, thus limiting their general application in controlling HFMD. Multivalent HFMD vaccines are suggested to have broad cross-neutralizing responses against these emerging enteroviruses., Areas Covered: We discuss the recent development of enterovirus A vaccines including the inactivated whole-virion vaccine and virus-like particle vaccine candidates and review the information of neutralization epitopes of these viruses., Expert Commentary: Evaluation of the efficacy and safety of the coxsackievirus vaccine and the multivalent HFMD vaccine candidates in clinical trials is urgently required. Epitopic analysis showed that common immunodominant sites exist across these enteroviruses. However, variations of amino acid residues in these regions limit the induction of cross-neutralization antibodies, and therefore, a multivalent HFMD vaccine is required for broad protection against HFMD. With the inclusion of major circulating viruses in the development of multivalent HFMD vaccines, an increase in the success in HFMD control is anticipated.

Introduction: Intranasal influenza vaccines are expected to confer protection among vaccine recipients by successful induction of mucosal immune response in the upper respiratory tract. Though only live attenuated influenza virus vaccines (LAIVs) are licensed and available for intranasal use in humans today, intranasal inactivated influenza vaccines (IIVs) are currently under reconsideration as a promising intranasal influenza vaccine., Areas Covered: This review addresses the history of intranasal IIV research and development, along with a summary of the studies done so far to address the mechanism of action of intranasal IIVs., Expert Commentary: From numerous in vitro and in vivo studies, it has been shown that intranasal IIVs can protect hosts from a broad spectrum of influenza virus strains. In-depth studies of the mucosal antibody response following intranasal IIV administration have also elucidated the detailed functions of secretory IgA (immunoglobulin A) antibodies which are responsible for the mechanism of action of intranasal vaccines. Safe and effective intranasal IIVs are expected to be an important tool to combat seasonal influenza.

Introduction: VaxigripTetra™ (IIV4; Sanofi Pasteur) is a quadrivalent split-virion influenza vaccine approved in Europe in 2016 for individuals ≥ 3 years of age. IIV4 builds on the well-established record of the trivalent split-virion influenza vaccine (Vaxigrip®). Areas covered: This literature review summarizes the rationale for developing quadrivalent influenza vaccines and discusses the phase III clinical trial results supporting the immunogenicity, safety, and tolerability of IIV4. Expert commentary: IIV4 is immunogenic and well tolerated. Adding a second B strain to the trivalent split-virion influenza vaccine provides a superior immune response for the additional strain but does not reduce the immune response for the three other strains or negatively affect the safety profile. By offering broader protection against co-circulating influenza B lineages, IIV4 has the potential to further reduce influenza-related morbidity and mortality beyond that achieved with trivalent vaccines.

Introduction: Epidemiologic evaluations of Streptococcus pneumoniae nasopharyngeal (NP) colonization and pneumococcal disease suggest that newer serotypes in future formulations of pneumococcal conjugate vaccines (PCVs) are needed and there may need to be continued reformulations because there are many new emerging serotypes expressed by pneumococci. Areas covered: Mechanisms of protection by next-generation whole-cell vaccine (WCV) and/or multi-component pneumococcal purified protein vaccines (PPVs) in development for prevention of pneumococcal infections. Expert commentary: A long-term strategy for prevention of pneumococcal disease will likely include WCV and PPVs. However these vaccines will impact disease pathogenesis in a different manner than PCVs. Prevention of pneumococcal NP colonization should not be expected, nor is it desirable because risks for NP colonization by other replacement organisms into the ecological niche vacated by all pneumococci may have consequences. The expression biology of capsule and surface protein antigens are phase dependent. Therefore, the immune response will be different and the mechanism of protection divergent. WCVs and PPVs may be alternative strategies in low income developing countries to protect against invasive disease and reduce NP carriage load.

Background: Viruses from two antigenically distinct influenza B strains have co-circulated since the mid-1980s, yet inactivated trivalent influenza vaccines (TIVs) with either the Victoria or Yamagata lineage could only provide limited protection from influenza B strain. Quadrivalent influenza vaccine (QIV) including both influenza B lineages can improve protection against circulating influenza B viruses., Methods: Participants >/ = 3 years of age were recruited, stratified by age, and then randomly allocated at a ratio of 2:1:1 to receive one-injection of the experimental QIV, TIV-Victoria (Vic) or TIV-Yamagata (Yam). The primary objective of this study was to demonstrate that the hemagglutination-inhibition (HI) antibodies induced by the QIV candidate are not inferior to the licensed TIVs., Results: First, 3661 participants received the inoculation. The QIV was found to be non-inferior to TIVs in terms of the geometric mean titers (GMTs) and seroconversion rates (SCRs) of the HI antibodies against shared strains 28 days after completion of inoculation, and was superior to the TIVs against the alternate B strain, which is absent from the TIVs. The occurrences of adverse events (AEs) post-vaccination were similar across the treatment groups., Conclusion: The experimental QIV showed good immunogenicity and an acceptable safety profile.

Introduction: Rapid development and production of vaccines against emerging diseases requires well established, validated, robust technologies to allow industrial scale production and accelerated licensure of products. Areas covered: A versatile Vero cell platform has been developed and utilized to deliver a wide range of candidate and licensed vaccines against emerging viral diseases. This platform builds on the 35 years' experience and safety record with inactivated whole virus vaccines such as polio vaccine. The current platform has been optimized to include a novel double inactivation procedure in order to ensure a highly robust inactivation procedure for novel emerging viruses. The utility of this platform in rapidly developing inactivated whole virus vaccines against pandemic (-like) influenza viruses and other emerging viruses such as West Nile, Chikungunya, Ross River and SARS is reviewed. The potential of the platform for development of vaccines against other emerging viruses such as Zika virus is described. Expert commentary: Use of this platform can substantially accelerate process development and facilitate licensure because of the substantial existing data set available for the cell matrix. However, programs to provide vaccines against emerging diseases must allow alternative clinical development paths to licensure, without the requirement to carry out large scale field efficacy studies.

Background: Inactivated Enterovirus 71 (EV71) vaccines showed significant efficacy against the diseases associated with EV71 and a neutralizing antibody (NTAb) titer of 1:16-1:32 was suggested as the correlates of the vaccine protection. This paper aims to further estimate the immunological surrogate endpoints for the protection of inactivated EV71 vaccines and the effect factors., Methods: Pre-vaccination NTAb against EV71 at baseline (day 0), post-vaccination NTAb against EV71 at day 56, and the occurrence of laboratory-confirmed EV71-associated diseases during a 24-months follow-up period were collected from a phase 3 efficacy trial of an inactivated EV71 vaccine. We used the mixed-scaled logit model and the absolute sigmoid function by some extensions in continuous models to estimate the immunological surrogate endpoint for the EV71 vaccine protection, respectively., Results: For children with a negative baseline of EV71 NTAb titers, an antibody level of 26.6 U/ml (1:30) was estimated to provide at least a 50% protection for 12 months, and an antibody level of 36.2 U/ml (1:42) may be needed to achieve a 50% protective level of the population for 24 months., Conclusion: Both the pre-vaccination NTAb level and the vaccine protective period could affect the estimation of the immunological surrogate for EV71 vaccine. A post-vaccination NTAb titer of 1:42 or more may be needed for long-term protection., Clinical Trial Registration: NCT01508247.

Introduction: Vaxigrip, a trivalent split-virion, inactivated vaccine available since 1968 has been in use longer than any other influenza vaccine. It is the most widely-used influenza vaccine, with more than 1.8 billion doses distributed in more than 120 countries. Areas covered: The significant body of evidence that confirms the efficacy, effectiveness, immunogenicity, and safety of Vaxigrip in healthy individuals of all ages and at-risk populations is summarized. The results from at least 15 randomized efficacy trials and 15 other studies have demonstrated that vaccination with Vaxigrip is efficacious against various clinical endpoints. It was estimated that more than 37 million laboratory-confirmed influenza episodes, 476,000 influenza-related hospitalizations, and 67,000 influenza-related deaths have been avoided by the more than 1.8 billion doses of Vaxigrip that have been distributed, emphasizing its important public health impact. Expert commentary: This strong evidence base in favor of Vaxigrip provides a robust foundation to support the implementation of the quadrivalent formulation. This quadrivalent formulation of Vaxigrip contains two A and two B influenza strains (VaxigripTetra), and has a similar immunogenicity and safety profile to the trivalent formulation while offering broader protection due to the addition of the second influenza B strain.

Introduction: Respiratory syncytial virus (RSV) infection is responsible for one-third of deaths of acute lower respiratory infection in children less than one-year-old. The formaldehyde-inactivated RSV vaccine trial conducted in the 1960s predisposed the vaccinees to more serious RSV infection instead of protection. Better understanding of the underlying mechanism is of critical importance for better designing of safe and effective RSV vaccines. Areas covered: PubMed was searched to review immunopathology induced by RSV vaccines. We intend to dissect the differences in clinical and pathological manifestations of enhanced respiratory disease (ERD) in different animal models in comparison with humans. Formaldehyde-inactivated RSV vaccine causes ERD in both humans and animals, while RSV vaccine without formaldehyde treatment could also induce similar disease in animals, suggesting multiple pathways may be involved. Expert commentary: Identification of biomarkers pertinent to clinical evaluation should be further explored for safety assessment of RSV vaccines in human trials.

Objectives: A CD1d-binding invariant natural killer T (iNKT)-cell stimulatory glycolipid, namely 7DW8-5, is shown to enhance the efficacy of radiation-attenuated sporozoites (RAS)-based malaria vaccine in mice. In the current study, we aim to determine whether 7DW8-5 can display a potent adjuvant effect in human immune system (HIS) mice., Methods: HIS-A2/hCD1d mice, which possess both functional human iNKT cells and CD8+ T cells, were generated by the transduction of NSG mice with adeno-associated virus serotype 9 expressing genes that encode human CD1d molecules and HLA-A*0201, followed by the engraftment of human hematopoietic stem cells. The magnitudes of human iNKT-cell response against 7DW8-5 and HLA-A*0201-restricted human CD8+ T-cell response against a human malaria antigen in HIS-A2/hCD1d mice were determined by using human CD1d tetramer and human HLA-A*0201 tetramer, respectively., Results: We found that 7DW8-5 stimulates human iNKT cells in HIS-A2/hCD1d mice, as well as those derived from HIS-A2/hCD1d mice in vitro. We also found that 7DW8-5 significantly increases the level of a human malarial antigen-specific HLA-A*0201-restricted human CD8+ T-cell response in HIS-A2/hCD1d mice., Conclusions: Our study indicates that 7DW8-5 can display a potent adjuvant effect on RAS vaccine-induced anti-malarial immunity by augmenting malaria-specific human CD8+ T-cell response.

Introduction: An intradermal version of Fluzone® split-virion inactivated trivalent influenza vaccine, containing 9 µg hemagglutinin per strain of A/H1N1, A/H3N2, and one B lineage virus (Fluzone Intradermal, Sanofi Pasteur), became available in the US during the 2011-2012 influenza season for adults 18-64 years of age. In advance of the 2015-2016 season, Fluzone Intradermal was replaced with Fluzone Intradermal Quadrivalent vaccine, which contains 9 µg hemagglutinin per strain of the two A-strain viruses and both B-strain lineage viruses (Victoria and Yamagata)., Areas Covered: This literature review summarizes the history and mechanism of intradermal vaccination, discusses the clinical trial results supporting the immunogenicity and safety of Fluzone Intradermal Quadrivalent vaccine, and describes the unique microinjection system used to deliver Fluzone Intradermal Quadrivalent. Expert commentary: Fluzone Intradermal Quadrivalent may boost confidence in influenza vaccination with the addition of a second B-lineage strain. By using an innovative microinjection system, the vaccine is also designed to address some of the logistic challenges faced by healthcare providers administering immunizations.

Background: We assessed the persistence of hemagglutinin inhibition (HAI) antibodies and the vaccine efficacy (VE) of trivalent inactivated influenza vaccine (IIV3) following vaccination of a cohort of pregnant South African women during a second influenza season., Methods: A cohort of women who participated in a randomized placebo-controlled trial on the safety, immunogenicity and efficacy of IIV3 in 2011 had HAI titers measured in 2012 and were monitored for influenza illness until the end of 2012., Results: The proportion of women with HAI titers ≥1:40 was significantly greater in vaccinees (63%) compared to placebo-recipients (22%; p < 0.001). VE in 2012 was 63.8% (95% confidence interval [95%CI]: -33.7%, 90.2%); combined VE for 2011 and 2012 was 58.3% (95%CI: 0.2%, 82.6%)., Conclusion: The majority of women who received IIV3 during pregnancy had HAI titers above the putative threshold for protection against influenza illness one year after vaccination and showed a trend towards protection against influenza disease.

Introduction: Enterovirus A71 (EV71) is the predominant causative agent of hand, foot, and mouth disease (HFMD), which is often associated with severe cases and even deaths. EV71-associated epidemics have emerged as a serious threat to public health, particularly in the Asia-Pacific region., Areas Covered: We searched PubMed using the terms 'enterovirus 71', 'hand, foot, and mouth disease', and 'vaccine', with no date or language restrictions for all publications before April 27, 2016. Among various vaccine candidates, the alum-adjuvant inactivated EV71 vaccines are most promising. Three alum-adjuvant inactivated EV71 vaccines developed by mainland China showed high efficacy, good immunogenicity persistence and acceptable safety profiles in clinical trials. Recently, two of these EV71 vaccines have been approved for marketing in China and the other one is undergoing the review process of licensure. In this manuscript, we summarized previous study results as well as discussed the regulatory affairs and post-market surveillances issues. Expert commentary: The marketing of EV71 vaccines is a milestone in the controlling of HFMD. International clinical trials are needed to further assess the efficacy and cross-immunogenicity. Establishing a sensitive pathogen monitoring system would be essential to monitor the variation of genotypes and control HFMD epidemics.

Foot-and-mouth disease (FMD) has been a major threat to livestock across the world. The predominant method of controlling this disease in endemic regions is through regular vaccination with inactivated vaccine. However, there are many limitations. For instance, cultivation of virulent FMD virus (FMDV) in the manufacturing units poses a risk of escape from production sites. Vaccines may sometimes contain traces of FMD viral non-structural proteins (NSPs), therefore, interfering with the NSP-based serological differentiation infected from vaccinated animals (DIVA). Moreover, vaccines are unable to eliminate virus from carrier animals. To address the shortcomings of inactivated vaccines, many efforts are currently devoted to develop novel vaccines including attenuated and/or marker inactivated vaccines, recombinant protein vaccines, synthetic peptide vaccines, and empty capsid vaccines. Here, we review the research progress of novel vaccines, problems that remain to be solved, and also raise some suggestions that would help in the development of FMD vaccines.

On December 3rd 2015, the China Food and Drug Administration (CFDA) approved the first inactivated Enterovirus 71 (EV71) whole virus vaccine for preventing severe hand, foot and mouth disease (HFMD). As one of the few preventive vaccines for children's infectious diseases generated by the developing countries in recent years, EV71 vaccine is a blessing to children's health in China and worldwide. However, there are still a few challenges facing the worldwide use of EV71 vaccine, including the applicability against various EV71 pandemic strains in other countries, international requirements on vaccine production and quality control, standardization and harmonization on different pathogen monitoring and detecting methods, etc. In addition, the affordability of EV71 vaccine in other countries is a factor to be considered in HFMD prevention. Therefore, with EV71 vaccine commercially available, there is still a long way to go before reaching effective protection against severe HFMD after EV71 vaccines enter the market. In this paper, the bottlenecks and prospects for the wide use of EV71 vaccine after its approval are evaluated.

Inactivated trivalent influenza vaccines (IIV3s) are designed to protect against illness caused by two influenza A virus subtypes and one influenza B virus lineage. They may provide inadequate protection due to the co-circulation of viruses from two antigenically distinct influenza B lineages. Incorporating strains from both B lineages as in inactivated quadrivalent influenza vaccines (IIV4s) reduces this risk. We summarize the evidence supporting two IIV4s manufactured by GSK Vaccines. Compared to IIV3s, these two IIV4s demonstrated noninferior immunogenicity against the shared influenza strains and superior immunogenicity for the strain of the additional B lineage, particularly in subjects who were seronegative for that B strain. One IIV4's efficacy in children aged 3-8 years was 55.4% against influenza of any severity and 73.1% against moderate-to-severe influenza. Both IIV4s were well-tolerated with a similar safety profile to IIV3s. These IIV4s are more likely than IIV3s to protect against the added influenza B strain.

Enterovirus A infections are the primary cause of hand, foot and mouth disease in infants and young children. Enterovirus 71 (EV71) and coxsackievirus A16 have emerged as neurotropic viruses responsible for severe neurological complications and a serious public health threat across the Asia-Pacific region. Formalin-inactivated EV71 vaccines have elicited protection against EV71 but not against coxsackievirus A16 infections. The development of a bivalent formalin-inactivated EV71/FI coxsackievirus A16 vaccine should be the next step towards that of multivalent hand, foot and mouth disease vaccines which should ultimately include other prevalent pathogenic coxsackieviruses and echovirus 30. This editorial summarizes the major challenges faced by the development of hand, foot and mouth disease vaccines.

With an estimated 68,000 cases each year, Japanese encephalitis (JE) is the leading cause of viral encephalitis in Asia. Vaccination against the disease is recommended for endemic populations and also for travelers at risk. Recently, a Vero cell-derived, inactivated, SA14-14-2 strain-based JE vaccine (JE-VC) became available for travelers from non-endemic regions, replacing the traditional mouse brain-derived vaccines. First licensed in 2009, JE-VC is currently available in Europe, the USA, Canada, Australia and several other countries. In 2013, the vaccine was approved by the European Medicines Agency and the US Food and Drug Administration for use in children. This review summarizes current data on the immunogenicity, safety and clinical use of JE-VC.

Notifications of infant deaths, assumed to be related to the introduction of new pentavalent DTwP-Hib-HBV childhood vaccines, caused, during 2008-2010 in few Asian countries, temporary interruptions of the respective vaccination programs. The sudden appearance of fatal cases was due to increased awareness/publicity and improved safety monitoring/reporting in countries with relatively high background infant mortalities. WHO investigations could not establish any causal relationships and vaccinations were again resumed. Recently, questions were raised in one concerned country as to why not to change to less reactogenic acellular pertussis (aP)-containing vaccines that are available in private practice and are generally perceived as 'better'. For resource-poor countries, the financial impacts render such a switch impossible and would also not be supported by external funding. Furthermore, it would be a disservice to the children, as in recent years evidence of inferior long-term efficacy of aP vaccines has accumulated. This report summarizes current knowledge on comparative whole-cell pertussis (wP) and aP vaccine performance, outlines the new July 2014 WHO guidance on the choice of pertussis vaccines and presents recent data on outbreak protection, antibody waning, long-term protection, wP-priming, pathogen adaptation, transmission and herd immunity.

Emerflu is an inactivated, split-virion pandemic preparedness vaccine, containing 30 μg of hemagglutinin (HA) and 600 μg of aluminum hydroxide adjuvant. It is administered in two doses, 3 weeks apart. Only moderate immunogenicity was evident from clinical studies with the vaccine in adults, and HA antibody responses were below the criteria established by the EMA and US FDA for licensure. With the exception of Australia, the vaccine remains unlicensed. Further clinical development appears to have been suspended, and newer adjuvants such as MF59 and AS03 have since demonstrated safety and superior immunogenicity with lower HA doses. Emerflu is symbolic of the failure of aluminum salts as an adjuvant for influenza vaccines. Reasons for this failure are unclear, and may reflect problems with the adjuvant-antigen complex or interference in the immune response by heterosubtypic immunity.

Influenza A and B infections cause significant morbidity and mortality. Over the past 30 years, two main influenza B strains have been circulating globally. The trivalent influenza vaccine used in the last 25 years contains one B strain, with approximately 31% of B strain disease coverage over the last 10 years. Fluarix quadrivalent vaccine, containing two A and two B strains, combines the components of two existing trivalent vaccines to prevent this mismatch. This review gives an overview of the published data about Fluarix quadrivalent vaccines, showing an immunogenicity and safety profile of the vaccine comparable with the two licensed trivalent vaccines containing the same strains, but with no evidence for efficacy in the literature. Future vaccines aim for a universal influenza vaccine that will give a long-lasting protection against all influenza strains.

Vaccination against influenza represents our most effective form of prevention. Historical approaches toward vaccine creation and production have yielded highly effective vaccines that are safe and immunogenic. Despite their effectiveness, these historical approaches do not allow for the incorporation of changes into the vaccine in a timely manner. In 2013, a recombinant protein-based vaccine that induces immunity toward the influenza virus hemagglutinin was approved for use in the USA. This vaccine represents the first approved vaccine formulation that does not require an influenza virus intermediate for production. This review presents a brief history of influenza vaccines, with insight into the potential future application of vaccines generated using recombinant technology.

The mosquito-borne Japanese encephalitis virus causes an estimated 50,000 cases in Asia, accounting for at least 10,000 deaths and 15,000 cases of neuropsychiatric sequelae. IXIARO (Intercell AG, Vienna, Austria), an inactivated, Vero cell-derived vaccine against Japanese encephalitis was introduced in 2009. The vaccine is highly immunogenic, showing significantly higher geometric mean antibody titers compared with previous, mouse brain-derived vaccines. Postmarketing studies have confirmed the excellent safety profile. Studies on children aged 2 months to 18 years have been published. Based on these data, positive opinion from the EMA for vaccination of children has recently been given. Since a safe and effective vaccine against Japanese encephalitis is now available, outdated guidelines and recommendations have to be revised: travelers to rural areas of Asia should generally be recommended vaccination.

Since 1970, aquaculture production has grown. In 2010, it had an annual average rate of 6.3% with 59.9 million tons of product and soon could exceed capture fisheries as a source of fishery products. However, the occurrence of viral diseases continues to be a significant limiting factor and its control is important for the development of this sector. In aquaculture farms, fish are reared under intensive culture conditions, and the use of viral vaccines has enabled an increase in production. Several types of vaccines and strategies of vaccination have been developed; however, this approach has not reached the expected goals in the most susceptible stage (fingerlings). Currently, there are inactivated and recombinant commercial vaccines, mainly for salmonids and cyprinids. In addition, updated genomic and proteomic technology has expedited the research and expansion of new vaccine models, such as those comprised of subunits or DNA. The objective of this review is to cover the various types of viral vaccines that have been developed and are available for bony fishes, as well as the advantages and challenges that DNA vaccines present for massive administration in a growing aquaculture, possible risks for the environment, the controversy regarding genetically modified organisms and possible acceptance by consumers.

HSV infections are prevalent worldwide. A vaccine to prevent genital herpes would have a significant impact on this disease. Several vaccines have shown promise in animal models; however, so far these have not been successful in human clinical studies. Prophylactic HSV vaccines to prevent HSV infection or disease have focused primarily on eliciting antibody responses. Potent antibody responses are needed to result in sufficiently high levels of virus-specific antibody in the genital tract. Therapeutic vaccines that reduce recurrences need to induce potent T-cell responses at the site of infection. With the increasing incidence of HSV-1 genital herpes, an effective herpes vaccine should protect against both HSV-1 and HSV-2. Novel HSV vaccines, such as replication-defective or attenuated viruses, have elicited humoral and cellular immune responses in preclinical studies. These vaccines and others hold promise in future clinical studies.

The aim of this review is to make researchers aware of the benefits of an efficient quality control system for prediction of a developed vaccine's efficacy. Two major goals should be addressed when inactivating a virus for vaccine purposes: first, the infectious virus should be inactivated completely in order to be safe, and second, the viral epitopes important for the induction of protective immunity should be conserved after inactivation in order to have an antigen of high quality. Therefore, some problems associated with the virus inactivation process, such as virus aggregate formation, protein crosslinking, protein denaturation and degradation should be addressed before testing an inactivated vaccine in vivo.

Enterotoxigenic Escherichia coli(ETEC) is the most common cause of bacterial diarrhea in children in Africa, Asia and Latin America and in travelers to these regions. Despite this, no effective vaccine for ETEC is available. ETEC causes disease by colonizing the small intestine with colonization factors, most of which are fimbriae, and production of heat-labile and/or heat-stable enterotoxins. Antibodies against heat-labile enterotoxin and the colonization factors have been shown to be protective, and local immunity in the gut seems to be of prime importance for protection. Hence, several inactivated and live candidate ETEC vaccines consisting of toxin antigens, alone or together with colonization factors, have been evaluated in clinical trials. In this review, the authors describe ETEC vaccine development in progress and the rationale for constructing different types of vaccines. They also discuss possibilities of enhancing immune responses to candidate ETEC vaccines, particularly in children.

A major challenge for global rabies prevention and control is the lack of sufficient and affordable high quality vaccines. Such candidates should be pure, potent, safe, effective and economical to produce, with broad cross-reactivity against viral variants of public health and veterinary importance. The history of licensed human vaccines reviewed herein demonstrates clearly how the field has evolved to the current state of more passive development and postexposure management. Modern cell culture techniques provide adequate viral substrates for production of representative verified virus seeds. In contrast to outdated nervous tissue-based rabies vaccines, once a suitable substrate is identified, production of high titer virus results in a major qualitative and quantitative difference. Given the current scenario of only inactivated vaccines for humans, highly cell-adapted and stable, attenuated rabies viruses are ideal candidates for consideration to meet the need for seed viruses in the future.

Japanese encephalitis virus (JEV), a flavivirus maintained in a zoonotic cycle and transmitted by the mosquito Culex tritaeniorhynchus, causes epidemics of encephalitis throughout much of Asia. Resident populations, including short- or long-term visitors to enzootic regions, are at risk of infection and disease. For the past several decades, killed viral vaccines prepared in tissue culture or mouse brain have been used effectively to immunize travelers and residents of enzootic countries. Cost, efficacy and safety concerns led to the development of a live-attenuated virus vaccine (SA14-14-2) and more recently, to the licensure in the USA, Europe, Canada, and Australia of a purified inactivated, tissue culture-based Japanese encephalitis vaccine (IXIARO(®), referred to as IC51; Intercell AG, Vienna, Austria). In addition, a live-attenuated yellow fever-Japanese encephalitis chimeric vaccine (IMOJEV™, referred to as Japanese encephalitis-CV; Sanofi Pasteur, Lyon, France) was recently licensed in Australia and is under review in Thailand. A broad portfolio of safe and effective Japanese encephalitis vaccines has become available to meet the needs of at-risk populations; when appropriately delivered, these new vaccines should greatly diminish the burden of disease.

Foot-and-mouth disease (FMD) is one of the most economically and socially devastating diseases affecting animal agriculture throughout the world. Although mortality is usually low in adult animals, millions of animals have been killed in efforts to rapidly control and eradicate FMD. The causing virus, FMD virus (FMDV), is a highly variable RNA virus occurring in seven serotypes (A, O, C, Asia 1, Sat 1, Sat 2 and Sat 3) and a large number of subtypes. FMDV is one of the most infectious agents known, affecting cloven-hoofed animals with significant variations in infectivity and virus transmission. Although inactivated FMD vaccines have been available for decades, there is little or no cross-protection across serotypes and subtypes, requiring vaccines that are matched to circulating field strains. Current inactivated vaccines require growth of virulent virus, posing a threat of escape from manufacturing sites, have limited shelf life and require re-vaccination every 4-12 months. These vaccines have aided in the eradication of FMD from Europe and the control of clinical disease in many parts of the world, albeit at a very high cost. However, FMDV persists in endemic regions impacting millions of people dependent on livestock for food and their livelihood. Usually associated with developing countries that lack the resources to control it, FMD is a global problem and the World Organization for Animal Health and the United Nations' Food Agriculture Organization have called for its global control and eradication. One of the main limitations to FMDV eradication is the lack of vaccines designed for this purpose, vaccines that not only protect against clinical signs but that can actually prevent infection and effectively interrupt the natural transmission cycle. These vaccines should be safely and inexpensively produced, be easy to deliver, and also be capable of inducing lifelong immunity against multiple serotypes and subtypes. Furthermore, there is a need for better integrated strategies that fit the specific needs of endemic regions. Availability of these critical components will greatly enhance the chances for the global control and eradication of FMDV.

The ability of Vibrio cholerae to persist in bodies of water will continue to confound our ability to eradicate cholera through improvements to infrastructure, and thus cholera vaccines are needed. We aim for an inexpensive vaccine that can provide long-lasting protection from all epidemic cholera infections, currently caused by O1 or O139 serogroups. Recent insights into correlates of protection, epidemiology and pathogenesis may help us design improved vaccines. This notwithstanding, we have come to appreciate that even marginally protective vaccines, such as oral whole-cell killed vaccines, if widely distributed, can provide significant protection, owing to herd immunity. Further efforts are still required to provide more effective protection of young children.

The first cases of pandemic influenza A (H1N1) 2009 infection were seen in Mexico in March 2009. Since then, it is thought to have been responsible for at least 18,337 deaths globally. Owing to the young age of fatalities, there have been an estimated 2 million years of life lost, which is comparable to the previous pandemics of 1957 and 1968. In this article, we consider the available data on a monovalent inactivated split-virion AS03-adjuvanted pandemic influenza A (H1N1) vaccine, Pandemrix™ (GlaxoSmithKline, Rixensart, Belgium). At present, Pandemrix appears to be highly immunogenic in all age groups, including children and infants under 3 years of age, with an acceptable safety profile in the context of an influenza pandemic. However, owing to the novel adjuvant, further studies on the safety, immunogenicity and vaccine effectiveness of Pandemrix together with robust post-marketing surveillance are required.

Seasonal influenza causes annual epidemics in temperate climates and is associated with economic costs, morbidity and mortality. Vaccination is the primary method of prevention. Intanza(®) (Sanofi Pasteur, Lyon, France) is a newly licensed, trivalent, inactivated influenza vaccine that is delivered intradermally with a proprietary micoinjection system. Two dosage formulations have been approved for use in Europe and Australia. The dosage level of 9 µg of hemagglutinin per strain is approved for persons 18-59 years of age, and its immunogenicity is noninferior to the standard dosage (15 µg per strain) administered intramuscularly. In addition, the dosage level of 15 µg of hemagglutinin per strain administered intradermally is approved for persons 60 years of age and older and has superior immunogenicity compared with that induced by the same dosage administered intramuscularly. Intanza has more frequent injection-site reactions than intramuscularly delivered vaccine, but it is safe and well tolerated. Intanza provides a new option for the prevention of influenza.

On 23 December 2009, the US FDA approved Fluzone&#x00AE; High Dose, a high-dose formulation of the trivalent inactivated influenza vaccine, for prevention of influenza in people 65 years of age and older. As it was approved via an accelerated process designed to allow expeditious availability of safe and effective products with promise to treat or prevent serious or life-threatening diseases, the manufacturer is required to conduct further studies to demonstrate effectiveness. Although these studies are underway, a recently completed randomized, controlled trial demonstrated that this vaccine, containing four-times more hemagglutinin than standard-dose inactivated influenza vaccines, can produce an enhanced immunologic response in subjects of 65 years of age and older, while maintaining a favorable safety profile. This article introduces the vaccine, presents currently available safety and immunogenicity data, discusses current recommendations for use, and proposes what we can expect in the coming years.

Rabies remains a global public health threat that kills more than 55,000 people per year. Rabies disproportionately affects children and, therefore, is ranked the seventh most important infectious disease due to years lost. Prevention of human rabies is accomplished by controlling rabies in domestic and wild animals, including the use of vaccination programs. The usefulness of human rabies vaccines is hampered by high cost, complicated vaccination regimens and lack of compliance, especially in areas of Africa and Asia where human rabies infections are endemic. A single-dose vaccine would greatly benefit efforts to combat this global health threat. However, a single-dose vaccine based on current inactivated vaccines does not appear feasible and other approaches are needed. Technology has advanced since modern human rabies vaccines were developed over 40 years ago. In addition, our understanding of immunological principles that influence the outcome of vaccination has increased. This article describes the current status of inactivated rabies virus vaccines and recent developments arising from the use of reverse genetics technologies designed to develop replication-deficient or single-cycle live rabies virus-based vectors for use as a single-dose rabies vaccine for humans.

Oral polio vaccine (OPV) has been an effective strategy since it was initiated almost five decades ago. However, concern regarding its collateral effects has been increasing in recent years among the scientific and policymaker community, since it has proved to be of risk for immunocompetent and immunocompromised individuals by causing cases and even outbreaks of poliomyelitis disease in countries where the virus is not circulating. Enhanced-potency inactivated polio vaccine (IPV), a safer, effective and inexpensive vaccine, has been available for the past couple of decades. Different points of view have emerged regarding stopping the use of OPV to start routine general IPV but, despite the evidence of OPVs derived and associated with unnecessary poliomyelitis cases, Central and South America are still lacking a strategy in place to make the switch from OPV to IPV, and there are no leading efforts to start this strategy. This review gives some evidence-based elements to help raise criteria regarding the best vaccine to choose and highlights the current need for strategic planning in Latin America to avoid more vaccine-associated paralytic poliomyelitis cases.

Enterovirus 71 (EV71) was first isolated in 1969 in California, USA. Several epidemic outbreaks with high mortality rates have occurred in European and Asian Countries (Bulgaria in 1975, Hungary in 1978, Malaysia in 1997, Taiwan in 1998 and China in 2008). EV71 CNS involvement may be associated with neurological sequelae, delayed neurodevelopment and reduced cognitive functioning. Since poliovirus was nearly eradicated by vaccination, EV71 is now considered as one of the top candidates for new vaccine development against human enteroviruses. Recently, several EV71 vaccine candidates, including live-attenuated virus, inactivated whole virus, recombinant viral protein, virus-like particle and DNA vaccines, have been evaluated in animals but no clinical trial has yet been conducted. Based on historical experiences with poliovirus vaccines and animal studies, the inactivated whole-virus vaccines are feasible and could be licensed readily, so these are targeted for preparing clinical trials in several organizations in Asia.

Shigellosis remains a formidable disease globally, with children of the developing world bearing the greatest number of infections. The need for an affordable, safe and efficacious vaccine has persisted for decades. Vaccines to prevent shigellosis can be divided into living and nonliving approaches. Several nonliving Shigella vaccines are currently at different stages of development and show substantial promise. Outlined here is an overview of multiple nonliving vaccine technologies, highlighting their current status and recent advances in testing. In addition, gaps in the knowledge base regarding immune mechanisms of protection are explored.

The mosquito-borne Japanese encephalitis virus (JEV) is a major threat to human health in Asia. An estimated 50,000 cases occur in the region, accounting for at least 10,000 deaths and 15,000 cases of neuropsychiatric sequelae. A new purified, inactivated JEV vaccine (IC51, Ixiaro) has been developed. Since early 2009, the vaccine has been licensed in Australia, the USA and Europe. A series of successful Phase III studies has been published. Results indicate a very good safety and efficacy profile. The vaccine promises to become a modern approach to active immunization against Japanese encephalitis. With the availability of a new product, wider use of Japanese encephalitis vaccine will be prudent in the future, and guidelines and recommendations should be revised.

Biosimilarity is a significant issue for vaccines and a reasonable approach to this could facilitate licensing of follow-on products of similar design. However, the definitions and guideline criteria developed for similar versions of biotherapeutics may be too restrictive for vaccines, as the molecular composition of their active substances can rarely be defined precisely, and immunogenicity is an essential rather than an undesirable characteristic. Similarity in antigenic composition may be more relevant. The criteria that determine biosimilarity need more careful definition; superficial similarity may conceal significant differences in performance that can only be disclosed by careful clinical evaluation. These issues have been reviewed in detail for current types of bacterial and viral vaccines. For truly biosimilar products, limited clinical studies could be acceptable provided that they permit side-by-side comparison with the original product or another suitable reference. The prospect of the development of biosimilar products also emphasizes the need for improved regulatory tests capable of detecting subtle but biologically significant differences in vaccines. The need for an acceptable definition of biosimilarity and guidelines relevant to vaccines is emphasized.

In this review, the current state of vaccine development against human severe acute respiratory syndrome (SARS) coronavirus, focusing on recently published data is assessed. We discuss which strategies have been assessed immunologically and which have been evaluated in SARS coronavirus challenge models. We discuss inactivated vaccines, virally and bacterially vectored vaccines, recombinant protein and DNA vaccines, as well as the use of attenuated vaccines. Data regarding the correlates of protection, animal models and the available evidence regarding potential vaccine enhancement of SARS disease are discussed. While there is much evidence that various vaccine strategies against SARS are safe and immunogenic, vaccinated animals still display significant disease upon challenge. Current data suggest that intranasal vaccination may be crucial and that new or combination strategies may be required for good protective efficacy against SARS in humans.

Over the past half-century, global use of highly effective vaccines against poliomyelitis brought this disease to the brink of elimination. Mounting evidence supports the argument that a high level of population immunity must be maintained after wild poliovirus circulation is stopped to preserve a polio-free status worldwide. Shifting factors in the risk-benefit-cost equation favor the creation of new poliovirus vaccines for use in the foreseeable future. Genetically stable attenuated virus strains could be developed for an improved oral poliovirus vaccine, but proving their safety and efficacy would be impractical owing to the enormous size of the clinical trials required. Novel versions of inactivated poliovirus vaccine that could be used globally should be developed. An improved inactivated poliovirus vaccine must be efficacious, inexpensive, safe to manufacture and easy to administer. Combination products containing inactivated poliovirus vaccine and other protective antigens should become part of routine childhood immunizations around the world.