Intradermal influenza vaccine and new devices: a promising chance for vaccine improvement

Introduction: The main public health strategy for reducing the influenza burden is annual vaccination. However, because the immune response in the elderly and frail subjects is known to be less vigorous than in younger adults, novel strategies have been explored in the last decade to augment immune response after immunization. These have included an increased dosage, multiple dose vaccinations, use of vaccine adjuvants and more efficient routes of vaccine delivery.

Areas covered: This review discusses recent advances in intradermally administered influenza vaccines with particular attention to immunogenicity and safety data from clinical trials performed using appropriate injection systems which, combining consistent injection depth and volume, safety, simplicity and ease-of-use, allowed large scale evaluation.

Expert opinion: Substantial experience has been accumulated with Intanza 9 and Intanza 15 μg/IDflu 15 μg, administered using BD's Soluvia^? device, and are the first intradermal trivalent inactivated split-virion influenza vaccines to be licensed for use in 18 – 59 year adults and in elderly people, respectively. Clinical data showed that they are safe and immunogenic and can offer significant advantages in terms of higher acceptability, higher immunogenicity in the elderly and dose-sparing in adults younger than 60 years when compared with intramuscularly administered vaccine.     

MF59-adjuvanted vaccine: a safe and useful tool to enhance and broaden protection against seasonal influenza viruses in subjects at risk

Importance of the field: Vaccination is universally considered as the most effective tool for the prevention of influenza, which represents a significant burden, both from a health-care and a socio-economic viewpoint. Conventional non-adjuvanted vaccines have shown suboptimal immunogenicity in the elderly, in patients with serious chronic diseases or the immunocompromised and in young children. The protection offered by non-adjuvanted vaccines may be further reduced by periodic antigenic drifts.

Areas covered in this review: Between the several strategies proposed to address the need for more immunogenic vaccines than the conventional ones, the most successful strategy is represented by the use of adjuvants. Since 1997, an MF59-adjuvanted subunit influenza vaccine has been licensed in several countries and used in the elderly worldwide. Available data on the safety, immunogenicity and effectiveness of this vaccine have been reported and discussed in details.

What the reader will gain: The MF59-adjuvanted vaccine has been shown to enhance immunogenicity and to confer cross-reactivity against heterologous influenza viral strains in the elderly, in adults with serious underlying medical conditions and in healthy infants and young children. Furthermore, its effectiveness has been demonstrated in older adults, reducing hospitalizations for pneumonia, cardiovascular and cerebrovascular diseases.

Take home message: The vaccine is safe, with an acceptable tolerability profile, thus representing a valid option to optimize the control of seasonal influenza.     

Production of adenovirus vectors and their use as a delivery system for influenza vaccines

Importance of the field: With the emergence of highly pathogenic avian influenza H5N1 viruses that have crossed species barriers and are responsible for lethal infections in humans in many countries, there is an urgent need for the development of effective vaccines which can be produced in large quantities at a short notice and confer broad protection against these H5N1 variants. In order to meet the potential global vaccine demand in a pandemic scenario, new vaccine-production strategies must be explored in addition to the currently used egg-based technology for seasonal influenza.

Areas covered in this review: Adenovirus (Ad) based influenza vaccines represent an attractive alternative/supplement to the currently licensed egg-based influenza vaccines. Ad-based vaccines are relatively inexpensive to manufacture, and their production process does not require either chicken eggs or labor-intensive and time-consuming processes necessitating enhanced biosafety facilities. Most importantly, in a pandemic situation, this vaccine strategy could offer a stockpiling option to reduce the response time before a strain-matched vaccine could be developed.

What the reader will gain: This review discusses Ad-vector technology and the current progress in the development of Ad-based influenza vaccines.

Take home message: Ad vector-based influenza vaccines for pandemic preparedness are under development to meet global vaccine demand.     

Glycoconjugate vaccines

Introduction: The global disease burden of serious bacterial infections is caused mainly by Haemophilus influenzae type b (Hib), Streptococcus pneumoniae and Neisseria meningitidis. Death or disability may be the potential aftermath of invasive infections with these pathogens. Active immunisation is the only rational approach in preventing such infections.

Areas covered: This review discusses the immunology of vaccination and describes the immunogenicity, safety and impact of glycoconjugate vaccines that have been developed against Hib, the most prevalent serotypes of S. pneumoniae and N. meningitidis serogroups A, C, W-135 and Y in all ages. The immune response to the plain polysaccharide vaccines that target the same pathogens is compared to that induced by the respective glycoconjugate vaccine formulations.

Expert opinion: Continued surveillance is necessary to recognise any epidemiological changes influenced by the impact of glycoconjugate vaccines and is crucial in guiding future vaccination strategies. Although, in general, the immunogenicity of glycoconjugate vaccines results in robust immune responses in all ages, subsequent booster doses may be necessary to sustain protection. Challenges in addressing inequities in vaccine availability between industrialised and developing countries are still there. The limitations of plain polysaccharide vaccines make immunisation with glycoconjugates a more sustainable long term option.     

Recombinant protein meningococcal serogroup B vaccine combined with outer membrane vesicles

Introduction: Meningococcal infection is a major cause of morbidity and mortality worldwide. Infection with Neisseria meningitidis is most common in young children, teenagers and people with certain medical conditions. Effective polysaccharide and glycoconjugate vaccines for serogroups A, C, W135 and Y have been developed. A similar capsular polysaccharide approach for serogroup B (MenB) has by most been judged as unsuitable, hence, no broad coverage vaccine has been licensed to date. The novel vaccine Bexsero (previously 4CMenB) has been developed and proven safe and immunogenic in clinical trials.

Areas covered: The authors outline the constituents of Bexsero and immunogenicity and safety data from preclinical and clinical trials published in peer-reviewed literature, meeting proceedings and publicly-available clinical trial websites from 2000 to 2010.

Expert opinion: Bexsero is well tolerated with a proven safety profile, and has demonstrated a robust immune response across different age groups against a range of diverse MenB strains. These data suggest that Bexsero has the ability to provide protection in infants, who are at the greatest risk of developing meningococcal disease.     

DNA vaccines against tuberculosis

Introduction: Tuberculosis (TB) remains a major health problem and novel vaccination regimens are urgently needed.

Areas covered: DNA vaccines against TB have been tested in various preclinical models and strategies have been developed to increase their immunogenicity in large animal species. DNA vaccines are able to induce a wide variety of immune responses, including CD8⁺ T-cell-mediated cytolytic and IFN-γ responses. DNA vaccination may be valuable in heterologous prime-boost strategies with the currently used bacillus Calmette–Guérin (BCG) vaccine. This approach could broaden the antigenic repertoire of BCG and enhance its weak induction of MHC class I-restricted immune responses.

Expert opinion: DNA vaccines offer a number of advantages over certain other types of vaccines, such as the induction of robust MHC class I-restricted cytotoxic T lymphocyte (CTL), their generic manufacturing platform and their relatively low manufacturing costs. Because of their strong potential for inducing memory responses, DNA vaccines are particularly suited for priming immune responses. Furthermore, DNA vaccine technology may help antigen discovery by facilitating screening of candidate vaccines. Co-administration of BCG with plasmid DNA coding for immunodominant, subdominant and phase-specific antigens, poorly expressed by BCG, may lead to the development of improved TB vaccines.     

Intradermal influenza vaccine and new devices: a promising chance for vaccine improvement

INTRODUCTION: The main public health strategy for reducing the influenza burden is annual vaccination. However, because the immune response in the elderly and frail subjects is known to be less vigorous than in younger adults, novel strategies have been explored in the last decade to augment immune response after immunization. These have included an increased dosage, multiple dose vaccinations, use of vaccine adjuvants and more efficient routes of vaccine delivery. AREAS COVERED: This review discusses recent advances in intradermally administered influenza vaccines with particular attention to immunogenicity and safety data from clinical trials performed using appropriate injection systems which, combining consistent injection depth and volume, safety, simplicity and ease-of-use, allowed large scale evaluation. EXPERT OPINION: Substantial experience has been accumulated with Intanza? 9 and Intanza 15 μg/IDflu? 15 μg, administered using BD's Soluvia? device, and are the first intradermal trivalent inactivated split-virion influenza vaccines to be licensed for use in 18 - 59 year adults and in elderly people, respectively. Clinical data showed that they are safe and immunogenic and can offer significant advantages in terms of higher acceptability, higher immunogenicity in the elderly and dose-sparing in adults younger than 60 years when compared with intramuscularly administered vaccine.     

Immunomodulatory properties of vitamins,flavonoids and plant oils and their potential as vaccine adjuvants and delivery systems

Introduction: During the past century, vaccinologists have attempted to mimic pathogens in their immune-enhancing capacity. This led to the development of life-saving vaccines based on live attenuated viruses, bacteria and toxoids. Hence, intense research in vaccine adjuvant discovery has focused on toll like receptors, mutant toxins and viral and bacterial vectors. Nutritive components such as vitamins and select polyphenols also possess immunomodulating properties without the potential toxic and adverse side effects of agents that mimic danger signals.

Areas covered: This review pertains to immunomodulatory properties of nutritive components, that is vitamins A, C, D, E, flavonoids and plant oils, as potential vaccine adjuvants and delivery systems, covering Pubmed publication searches from 1980 through 2011.

Expert opinion: This relatively unexplored field of the potential of nutritive components as vaccine adjuvants holds great promise to promote the development of effective and above all safe vaccines. Hence the future focus should be placed on enhancing their efficacy, mainly through novel approaches in designing structural derivatives, formulations, delivery systems and routes of administration. As safety has been the major issue in development of novel vaccines, this new approach will probably result in new discoveries in designing safe and effective vaccines.     

Recent advances with a virosomal hepatitis A vaccine

Background: Epaxal^®, a virosomal vaccine against hepatitis A virus (HAV) infection, has been in use for nearly 15 years, especially among at-risk adults. Recent studies have shown that it is also a potent vaccine for children. Objective: To summarise recent advances of Epaxal^® Junior (0.25 ml, paediatric formulation). Methods: Published papers reporting results on the virosomal HAV vaccine were abstracted and reviewed. Results/conclusion: In a comparative randomised trial, the paediatric dose was found to be highly immunogenic and non-inferior to the standard dose with respect to seroprotection rates. The concomitant administration of virosomal HAV vaccine with routine childhood vaccines was investigated in another trial. The virosomal HAV vaccine did not interact with the antibody response of routine childhood vaccines which in turn did not reduce the antibody response to HAV. In countries that recommend immunisation against hepatitis A, this virosomal vaccine is an excellent candidate with few side effects at the site of injection.     

MUC1-based recombinant Bacillus Calmette–Guerin vaccines as candidates for breast cancer immunotherapy

Importance of the field: The challenge in breast cancer vaccine development is to find the best combination of antigen, adjuvant and delivery system to produce a strong and long-lasting immune response. Mucin 1 (MUC1) is a potential candidate target for breast cancer immunotherapy. Bacillus Calmette–Guerin (BCG) is used widely in human vaccines. Furthermore, it can potentially offer unique advantages for developing a safe and effective multi-vaccine vehicle. Due to these properties, the development of MUC1 based recombinant BCG (rBCG) vaccines for breast cancer immunotherapy has gained great momentum in recent years.

Areas covered in this review: Our aim is to discuss the recent progress in MUC1-based breast cancer immunotherapy and to highlight the advantages of MUC1-based rBCG vaccines as the new breast cancer vaccines.

What the reader will gain: Several promising MUC1-based rBCG vaccines have been shown to induce MUC1-specific antitumor immune responses in pre-clinical studies. This review updates and evaluates this very important and rapidly developing field, and provides a critical perspective and information source for its potential clinical applications.

Take home message: MUC1-based rBCG vaccines have been shown to elicit an effective anti-tumor immune response in vivo demonstrating its potential utility in breast cancer treatment.     

Immunotherapy for metastatic prostate cancer: where are we at with sipuleucel-T?

Importance of the field: Prostate cancer is the leading malignancy in North American men and despite improvements in treatments 20 – 30% of patients will relapse. Immunotherapy using activated mononuclear cells is a way to harness the body's adaptive immune response to fight metastatic prostate cancer.

Areas covered in this review: In 2005, at least 10 therapeutic cancer vaccines, designed to confer active, specific immunotherapy against tumor-associated antigens, were in clinical trials. These covered potential fields of immunological strategy to overcome castration-resistant prostate cancer.

What the reader will gain: A literature review was performed using the search terms sipuleucel-T, Provenge and APC8015 or APC-8015, and restricted to English language articles from 2000 to 2010. The immunological design and development of sipuleucel-T are summarized. The efficacy and safety of sipuleucel-T are discussed based on current data from clinical trials. Ongoing clinical trials involving sipuleucel-T are summarized.

Take home message: Efficacy and safety with sipuleucel-T has been demonstrated in Phase I/II trials. The latest data from a Phase III trial shows that sipuleucel-T has met the primary endpoint of survival benefit. Further work is needed to understand the mechanisms behind cancer vaccine failure and elucidate the population for whom this vaccine will be suitable.     

AE37: a novel T-cell-eliciting vaccine for breast cancer

Introduction: Immunotherapy, including vaccines targeting the human EGFR2 (HER-2/neu) protein, is an active area of investigation in combatting breast cancer. Several vaccines are currently undergoing clinical trials, most of which are CD8⁺ T-cell-eliciting vaccines. AE37 is a promising primarily CD4⁺ T-cell-eliciting HER-2/neu breast cancer vaccine currently in clinical trials.

Areas covered: This article reviews preclinical investigations as well as findings from completed and ongoing Phase I and Phase II clinical trials of the AE37 vaccine.

Expert opinion: Clinical trials have shown the AE37 vaccine to be safe and capable of generating peptide-specific, durable immune responses. This has been shown in patients with any level of HER-2/neu expression. Early clinical findings suggest there may be benefit to AE37 vaccination in preventing breast cancer recurrence.     

Disparities in co-payments for influenza vaccine among the elderly,during the COVID-19 pandemic in Japan

IntroductionSeasonal influenza vaccination for the elderly is highly recommended during the COVID-19 pandemic. In Japan, the amount of subsidy for influenza differs among municipalities. Thus, we investigated the amount of and variation in subsidy for influenza vaccination for the elderly in 2020.MethodsThis was an ecological study of 1,922 municipalities in Japan. The amount of subsidy for influenza vaccines for the elderly in each municipality was surveyed through websites or via telephone. Geographic and financial data for municipalities and prefectures were obtained from the open data. The amount of co-payment for the influenza vaccine and the geographical and financial status of each municipality were compared, according to the aging rate. Univariate logistic regression analysis was performed to explore factors related to the free influenza vaccine.ResultsMunicipalities with higher aging rates tended to have higher median co-payments for vaccines in 2020. (0 yen vs 1000 yen, p < 0.001) In addition, they tended to have worse financial conditions and lower per capita incomes. A similar trend was observed in the analysis by prefecture, i.e., a higher influenza mortality rate in prefectures with a higher aging rate. Despite having lower incomes, municipalities and prefectures with higher aging populations had higher mortality rates from influenza and higher co-payments for influenza vaccination.ConclusionsIn Japan, there is a disparity among elderly people; areas with an aging population have higher co-payments for influenza vaccines despite lower incomes, suggesting that the government needs to implement corrective measures to reduce this disparity.     

Development of pneumococcal vaccines over the last 10 years

Introduction: Although significant improvements in the prevention of pneumococcal infections have been achieved in recent years, Streptococcus pneumoniae remains a leading cause of morbidity and mortality. To prevent S. pneumoniae infections, vaccines have been developed for several years.

Areas covered: In this review, the most important emerging problems regarding pneumococcal conjugate vaccines (PCVs) are discussed in addition to the status of new vaccine design and development. Given the medical, social and economic relevance of pneumococcal diseases, the availability of effective and safe vaccines against S. pneumoniae is a key objective of public health.

Expert opinion: Protein vaccines using agents different from capsular polysaccharides (CPs) or whole-cell vaccines seem to induce a broader immune response than PCVs and theoretically offer definitive solutions, as they can stimulate both humoral and cellular immunity. Moreover, these vaccines, particularly the whole-cell vaccine, are simpler to produce and significantly less expensive. However, the development of these preparations is very far from completion. It is highly likely that for a long time, no new safe and effective pneumococcal vaccines will be available. The best formulation of new pneumococcal vaccines has not been established. Consequently, an effort towards the expanded use of the available vaccines has to be made.     

An update on vaccines for tuberculosis – there is more to it than just waning of BCG efficacy with time

Introduction: Apart from better diagnostics and new anti-microbial drugs, an effective vaccine for tuberculosis is urgently needed to halt this poverty-related disease, afflicting millions of people worldwide.

Areas covered: After a general introduction on the global threat of tuberculosis, the pros and cons of the existing M. bovis BCG vaccine are discussed. As the correlates of protection against tuberculosis remain largely unknown, new findings in biomarker research are described. Next, an update on the ongoing Phase I and Phase II clinical trials is given. Finally, some of the most promising novel pre-clinical developments using live attenuated vaccines, sub-unit vaccines, prime-boost strategies, and new vaccination routes are discussed. The field has made considerable progress and 12 vaccine candidates have now actually entered Phase I or Phase IIa and IIb clinical trials.

Expert opinion: It is argued that the variable protection conferred by the existing BCG vaccine against reactivation of latent TB is caused not only by waning of its efficacy with time but also by its weak induction of MHC class I restricted responses. Prime-boost strategies based on the actual BCG vaccine may not be sufficient to overcome this hurdle. The use of plasmid DNA vaccination might offer a solution.     

Mucosal HIV transmission and vaccination strategies through oral compared with vaginal and rectal routes

Importance of the field: There are currently over thirty million people infected with HIV and there are no vaccines available to prevent HIV infections or disease. The genitourinary, rectal and oral mucosa are the mucosal HIV transmission routes. An effective vaccine that can induce both systemic and local mucosal immunity is generally accepted as a major means of protection against mucosal HIV transmission and AIDS.

What the reader will gain: Structure and cells that comprise the oral, vaginal and rectal mucosa pertaining to HIV transmission and vaccination strategies through each mucosal route to prevent mucosal and systemic infection will be discussed.

Areas covered in this review: Covering publications from 1980s through 2010, mucosal transmission of HIV and current and previous approaches to vaccinations are discussed.

Take home message: Although oral transmission of HIV is far less common than vaginal and rectal transmissions, infections through this route do occur through oral sex as well as vertically from mother to child. Mucosal vaccination strategies against oral and other mucosal HIV transmissions are under intensive research but the lack of consensus on immune correlates of protection and lack of safe and effective mucosal adjuvants and delivery systems hamper progress towards a licensed vaccine.     

Respiratory syncytial virus vaccine: where are we now and what comes next?

ABSTRACT

Introduction: Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection in infants and elderly and to date, there is no safe or effective vaccine against RSV.

Areas Covered: This review provides a roadmap to RSV vaccine development. It is a journey spanning over more than half a century from the initial disappointment with inactivated formalin vaccine to the current advancements in vaccine technology. We highlight the important aspects of RSV structural biology and protective immune response. We include discussion of newer fusion glycoprotein immune targets and current vaccine candidates. We used Pub Med and Medline resources for literature search.

Expert opinion: A resurgence of information on the burden related to RSV infection coupled with the newer understanding of the molecular mechanism of RSV infection has reignited a tremendous activity in RSV vaccine discovery. The vaccine pipeline is diverse and target populations are varied, thus making the goal of a safe and effective RSV vaccine in the future within reach.     

Therapeutic vaccines for leishmaniasis

Introduction: Numerous therapeutic strategies are used to treat leishmaniasis. The treatment of cutaneous leishmaniasis (CL) is solely depends on antimonate derivatives with safety issues and questionable efficacy and there is no fully effective modality to treat CL caused by Leishmania tropica and Leishmania braziliensis.

Areas covered: There is no prophylactic vaccine available against any form of leishmaniasis. Immunotherapy for CL has a long history; immunotherapy trials of first and second generation vaccines showed promising results. The current article briefly covers the prophylactic vaccines and explains different immunotherapy strategies that have been used to treat leishmaniasis. This paper does not include experimental vaccines and only lays emphasis on human trials and those vaccines which reached human trials.

Expert opinion: Immunotherapy is currently used to successfully treat several disorders; Low cost, limited side effects and no possibility to develop resistance make immunotherapy a valuable choice especially for infectious disease with chemotherapy problems. Efforts are needed to explore the immunological surrogate marker(s) of cure and protection in leishmaniasis and overcome the difficulties in standardization of crude Leishmania vaccines. One of the reasons for anti-leishmaniasis vaccine failure is lack of an appropriate adjuvant. So far, not enough attention has been paid to develop vaccines for immunotherapy of leishmaniasis.     

Prepandemic H5N1 influenza vaccine adjuvanted with AS03: a review of the pre-clinical and clinical data

Background: Universal and timely administration of a prepandemic vaccine is considered to be one of the most effective measures to reduce the incidence of pandemic influenza infection and consequently its morbidity and mortality. Objectives: To provide the reader with basic insights into influenza virus infections, the threat of a pandemic and the challenges it poses for vaccine development. Methods: This review summarizes the reported preclinical and clinical data obtained with the prepandemic H5N1 vaccine adjuvanted with AS03. Results: The AS03-adjuvanted prepandemic H5N1 influenza vaccine allows for antigen sparing, has a good safety and acceptable reactogenicity profile, induces an immune response that not only meets all European Committee for Medicinal Products (CHMP) and FDA requirements for the vaccine strain but also generates neutralizing antibodies that broadly cross-react against H5N1 drift strains, and finally conveys protection in a ferret model against lethal challenges with homologous and heterologous H5N1 viruses.