Reactions to small pox vaccine in naïve and previously-vaccinated individuals

Two hundred health care workers in England and Wales were vaccinated with the Lister/Elstree strain of the vaccinia virus, and completed health diaries for 21 days or until the lesion had scabbed over. Pain and temperature were measured daily, and all other symptoms recorded freehand by the vaccinee. One hundred and forty two (71%) vaccinees reported pain, of which 25% considered it to be moderate or severe; 32 vaccinees (16%) recorded a temperature of >37.7 degrees C, two of which exceeded 39 degrees C. Other, mainly trivial, adverse events were common; itch was reported in 72%, erythema in 27%, axillary pain or lymphadenopathy in 38%, malaise or flu-like symptoms in 40% and headache in 23%. The incidences of minor adverse events were lower in re-vaccinees, compared with na?ve vaccine recipients, significantly so in the case of erythema and general malaise (p=0.001 and 0.006, respectively), perhaps reflecting pre-existing immunity. Major adverse events occurred in two vaccinees (hospital admission, one with cellulitis and one with headache and possible encephalitis), and a further five were treated with antibiotics for local cellulitis. This is the first study to report results derived from active follow-up by diaries in recipients of the Lister/Elstree strain of vaccinia, and to document reductions in trivial adverse events in re-vaccinees.     

Antibody and cellular immune responses of naïve mares to repeated vaccination with an inactivated equine herpesvirus vaccine

Equine herpesvirus type 1 (EHV-1) continues to cause severe outbreaks of abortions or myeloencephalopathy in horses despite widely used vaccination. The aim of this work was to determine the effects of frequent vaccination with an inactivated EHV vaccine on immune development in horses. Fifteen EHV-1 naïve mares were vaccinated a total of 5 times over a period of 8 months with intervals of 20, 60, 90 and 60 days between vaccine administrations. Total antibody and antibody isotype responses were evaluated with a new sensitive EHV-1 Multiplex assay to glycoprotein C (gC) and gD for up to 14 months after initial vaccination. Antibodies peaked after the first two vaccine doses and then declined despite a third administration of the vaccine. The fourth vaccine dose was given at 6 months and the gC and gD antibody titers increased again. Mixed responses with increasing gC but decreasing gD antibody values were observed after the fifth vaccination at 8 months. IgG4/7 isotype responses mimicked the total Ig antibody production to vaccination most closely. Vaccination also induced short-lasting IgG1 antibodies to gC, but not to gD. EHV-1-specific cellular immunity induced by vaccination developed slower than antibodies, was dominated by IFN-γ producing T-helper 1 (Th1) cells, and was significantly increased compared to pre-vaccination values after administration of 3 vaccine doses. Decreased IFN-γ production and reduced Th1-cell induction were also observed after the second and fourth vaccination. Overall, repeated EHV vaccine administration did not always result in increasing immunity. The adverse effects on antibody and cellular immunity that were observed here when the EHV vaccine was given in short intervals might in part explain why EHV-1 outbreaks are observed worldwide despite widely used vaccination. The findings warrant further evaluation of immune responses to EHV vaccines to optimize vaccination protocols for different vaccines and horse groups at risk.     

Safety and immunogenicity of the Na-APR-1 hookworm vaccine in infection-naïve adults

BackgroundThe Necator americanus hemoglobinase, aspartic protease-1 (Na-APR-1), facilitates the ability of adult hookworms to parasitize the intestine of their human hosts. A recombinant version of APR-1 protected laboratory animals against hookworm infection by inducing neutralizing antibodies that block the protein’s enzymatic activity and thereby impair blood feeding. A catalytically inactive version of the wild-type hemoglobinase (Na-APR-1(M74)) was expressed by infiltrating Nicotiana benthamiana tobacco plants with an Agrobacterium tumefaciens strain engineered to express the vaccine antigen, which was adjuvanted with aluminum hydroxide adjuvant (Alhydrogel).MethodsAn open-label dose-escalation Phase 1 clinical trial was conducted in 40 healthy, hookworm-naïve adult volunteers in the United States. Participants received 30 or 100 µg of recombinant Na-APR-1(M74) with Alhydrogel or with Alhydrogel co-administered with one of two doses (2.5 or 5.0 µg) of an aqueous formulation of Glucopyranosyl Lipid A (GLA-AF). Intramuscular injections of study vaccine were administered on days 0, 56, and 112.ResultsNa-APR-1(M74)/Alhydrogel was well-tolerated; the most frequent adverse events were mild or moderate injection site tenderness and pain, and mild or moderate nausea and headache. No serious adverse events or adverse events of special interest related to vaccination were observed. Significantly higher levels of antigen-specific IgG antibodies were induced in those who received 100 µg Na-APR-1(M74) than those who received 30 µg of antigen. Adding GLA-AF to Na-APR-1(M74)/Alhydrogel resulted in higher levels of IgG against Na-APR-1(M74) in both the 30 and 100 µg Na-APR-1(M74) groups in comparison to the non-GLA formulations at the same antigen dose.ConclusionsVaccination of hookworm-naïve adults with recombinant Na-APR-1(M74) was well-tolerated, safe, and induced significant IgG responses against the vaccine antigen Na-APR-1(M74). Given these favorable results, clinical trials of this product were initiated in hookworm-endemic areas of Gabon and Brazil.     

Pandemic H1N1 in Canada and the use of evidence in developing public health policies – A policy analysis

When responding to a novel infectious disease outbreak, policies are set under time constraints and uncertainty which can limit the ability to control the outbreak and result in unintended consequences including lack of public confidence. The H1N1 pandemic highlighted challenges in public health decision-making during a public health emergency. Understanding this process to identify barriers and modifiable influences is important to improve the response to future emergencies. The purpose of this study is to examine the H1N1 pandemic decision-making process in Canada with an emphasis on the use of evidence for public health decisions. Using semi-structured key informant interviews conducted after the pandemic (July–November 2010) and a document analysis, we examined four highly debated pandemic policies: use of adjuvanted vaccine by pregnant women, vaccine priority groups and sequencing, school closures and personal protective equipment. Data were analysed for thematic content guided by Lomas' policy decision-making framework as well as indicative coding using iterative methods. We interviewed 40 public health officials and scientific advisors across Canada and reviewed 76 pandemic policy documents. Our analysis revealed that pandemic pre-planning resulted in strong beliefs, which defined the decision-making process. Existing ideological perspectives of evidence strongly influenced how information was used such that the same evidentiary sources were interpreted differently according to the ideological perspective. Participants recognized that current models for public health decision-making failed to make explicit the roles of scientific evidence in relation to contextual factors. Conflict avoidance theory explained policy decisions that went against the prevailing evidence. Clarification of roles and responsibilities within the public health system would reduce duplication and maintain credibility. A more transparent and iterative approach to incorporating evidence into public health decision-making that reflects the realities of the external pressures present during a public health emergency is needed.     

Efficacy of a live attenuated tetravalent candidate dengue vaccine in naïve and previously infected cynomolgus macaques

The development of a safe and effective vaccine against dengue is a public health priority. Attempts to evaluate candidate vaccine formulations in human volunteers were largely unsuccessful, at least in part due to too high reactogenicity of some of the candidate vaccines tested. We evaluated a live attenuated tetravalent dengue vaccine candidate in flavivirus na?ve and dengue virus type 3 immune non-human primates. Immune responses were measured both at the humoral and the cellular level and the efficacy of this vaccine candidate was evaluated by challenging the vaccinated animals with dengue virus type 4. Humoral and cellular immune responses upon vaccination were similar to those described after natural infection in humans. All animals were protected from developing viremia upon challenge infection. In addition, primary dengue virus type 3 infection of macaques neither influenced the immune response upon vaccination, nor interfered with vaccine-induced protection from dengue virus type 4 challenge infection. The data suggest that the live attenuated tetravalent vaccine candidate used is promising and warrant further safety and efficacy testing in clinical trials.     

Dynamics and molecular evolution of HIV-1 strains in Sicily among antiretroviral naïve patients

HIV-1 subtype B is the most frequent strain in Sicily. To date, there is no available data about the genetic diversity of HIV-1 viral strains circulating in Sicily among antiretroviral (ARV) naïve subjects and the role of immigration as potential determinant of evolutionary dynamics of HIV-1 molecular epidemiology.For this purpose, HIV-1 polymerase (pol) sequences obtained from 155 ARV naïve individuals from 2004 to 2009 were phylogenetically analysed.The overall rate of HIV-1 non-B infections was 31.0% (n = 48/155), increasing from 7.8% in 2004–2006 to 40.9% in 2009, and about one-third were identified as unique recombinant forms.CRF02_AG was the prevalent non-B clade (n = 28/48, 58.3%), while subtype C-related strains were responsible for about 30% HIV-1 infections.Non-B viruses strictly associated with heterosexual transmission (85.4%) and were mostly found among immigrants (77.1%). Phylogenetic analysis of non-B sequences found in foreign-born subjects was geographically correlated to the respective country of origin. Moreover, the detection of non-B viral variants in the autochthonous population may support an increasing genetic diversity in Sicily as well as a local circulation of HIV strains also uncommon in our country.In Sicily, HIV-1 epidemic is still mostly attributable to the B subtype. Nevertheless, migration and population movements are progressively introducing novel HIV-1 subtypes causing a continuous increase of HIV-1 molecular dynamic at local level. Molecular surveillance is needed to monitor the genetic evolution of HIV-1 epidemic.     

Detailed kinetics of immune responses to a new cell culture-derived smallpox vaccine in vaccinia-naïve adults

The aim of the present study was to investigate the kinetics of humoral and cell-mediated immune responses to a new cell culture-derived smallpox vaccine (CJ-50300, CJ Corporation, South Korea) in 18 vaccinia-na?ve volunteers. All subjects achieved positive humoral immune responses (plaque reduction neutralizing antibody assay) 28 days after vaccination, and cell-mediated immune responses (ELISPOT assay) 14 days after vaccination. Humoral immune responses increased up to 28 days after vaccination and were maintained up to 56 days after vaccination. In contrast, cell-mediated immune responses increased up to 14 days after vaccination and steadily decreased to 56 days after vaccination [Clinical Trial No. NCT 00336635].     

Safety of Pfizer-BioNTech vaccine in a cohort of healthcare providers: Differences between naïve and previously infected by SARS-CoV-2

IntroductionThe Spanish Society of Immunology recently warned that a history of past COVID-19 could result in a higher incidence of adverse events (AEs) related to vaccination. We set out to analyze whether there were any differences in AEs between healthcare workers vaccinated for COVID-19 (either after the first or second dose) who had had a prior diagnosis SARS-CoV-2 infection at any time compared to those who had not had COVID-19 before vaccination.MethodsThis was a retrospective cohort study in a population of healthcare workers. AEs related to the first and second doses of the Pfizer vaccine were recorded. We compared the incidence of AEs and compared individuals with 0–3 different AEs to those with 4 or more AEs. The relative risks (RR) and their 95% confidence intervals were calculated.ResultsPast infection was associated with having more AEs after the first dose (p < 0.001), but not the second one (p = 0.476), as well as a higher incidence of AEs (p < 0.001). Common AEs that were statistically associated with past COVID infection included arthralgia, asthenia, fever, chills, headache, and myalgia (p ≤ 0.001). The RR for having an increased absolute number of different AEs was 1.18 (95 %CI [1.05, 1.33]) after the first dose and 1.05 (95 %CI [0.96, 1.14]) after the second dose. The maximum number of days between past infection and vaccination was 306.ConclusionsOur results showed that the incidence of AEs was higher in individuals with a history of prior COVID-19 infection.     

n-3 PUFA fail to affect in vivo, antigen-driven CD8+T-cell proliferation in the spleen of naïve mice

One of the most frequently reported immunomodulatory actions of n-3 PUFA is their ability to diminish in vitro lymphocyte proliferation. The purpose of this study was to determine if n-3 PUFA intake affects the kinetics or magnitude of the antigen-driven expansion of CD8(+)T-lymphocytes in vivo. In this study we utilized a well-characterized model of T-cell immunity (i.e. infection with the intracellular bacterium, Listeria monocytogenes). Weanling BALB/c mice were fed one of two experimental diets that differed solely in fat source. Our control diet contained lard (180 g/kg) and was devoid of long-chain n-3 PUFA. The experimental diet contained 150 g/kg menhaden fish oil and 30 g/kg corn oil, thus providing approximately 8 % of energy from long-chain n-3 PUFA. After 4 weeks, mice were infected intravenously with 10(6) colony-forming units of actA-deficient L. monocytogenes. Clonal expansion of antigen-specific CD8(+)T-cells in the spleen was measured at 5, 7, 9 and 14 d post-challenge using a class I MHC tetramer loaded with the immunodominant peptide from this pathogen (i.e. K(d):LLO91-99). We report that feeding mice a diet rich in n-3 fatty acids did not significantly impact either the kinetics or magnitude of in vivo, antigen-driven expansion of CD8(+)T-cells. Furthermore, contraction of this T-cell population was not affected by n-3 PUFA treatment. To our knowledge this is the first time MHC tetramers have been used to investigate the influence of n-3 PUFA on in vivo CD8(+)T-cell proliferation.     

Use of ENABL® adjuvant to increase the potency of an adenovirus-vectored foot-and-mouth disease virus serotype A subunit vaccine

A foot-and-mouth disease (FMD) recombinant subunit vaccine formulated with a lipid/polymer adjuvant was evaluated in two vaccine efficacy challenge studies in steers. The vaccine active ingredient is a replication-deficient human adenovirus serotype 5 vector encoding the FMD virus (FMDV) A24/Cruzeiro/BRA/55 capsid (AdtA24). In the first study, AdtA24 formulated in ENABL® adjuvant was compared to a fourfold higher dose of AdtA24 without adjuvant. Steers vaccinated with AdtA24 + ENABL® adjuvant developed a significantly higher virus neutralizing test (VNT) antibody titer and an improved clinical response following FMDV A24/Cruzeiro/BRA/55 intradermal lingual challenge at 14 days post-vaccination (dpv) than steers vaccinated with the active ingredient alone. In the second study, vaccination with AdtA24 formulated in ENABL® at the same dose used in the first study, followed by FMDV A24/Cruzeiro/BRA/55 challenge on 7 or 14 dpv, prevented clinical FMD in all steers and conferred 90% protection against viremia. In addition, post-challenge FMDV titers in nasal samples from vaccinated steers compared to unvaccinated steers were significantly reduced. In both studies, none of the AdtA24 vaccinated steers developed antibodies to the FMDV non-structural proteins prior to challenge with FMDV, indicative of the capacity to differentiate infected from vaccinated animals (DIVA). These results demonstrate that administration of AdtA24 formulated in ENABL® adjuvant lowered the protective dose and prevented clinical FMD following exposure of vaccinated steers to virulent FMDV at 7 or 14 dpv.     

Vaccinating healthcare workers against influenza to protect the vulnerable--is it a good use of healthcare resources? A systematic review of the evidence and an economic evaluation

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.     

Novel hemagglutinin nanoparticle influenza vaccine with Matrix-M™ adjuvant induces hemagglutination inhibition,neutralizing, and protective responses in ferrets against homologous and drifted A(H3N2) subtypes

Influenza viruses frequently acquire mutations undergoing antigenic drift necessitating annual evaluation of vaccine strains. Highly conserved epitopes have been identified in the hemagglutinin (HA) head and stem regions, however, current influenza vaccines induce only limited responses to these conserved sites. Here, we describe a novel seasonal recombinant HA nanoparticle influenza vaccine (NIV) formulated with a saponin-based adjuvant, Matrix-M™. NIV induced hemagglutination inhibition (HAI) and microneutralizing (MN) antibodies against a broad range of influenza A(H3N2) subtypes. In a comparison of NIV against standard-dose and high-dose inactivated influenza vaccines (IIV and IIV-HD, respectively) in ferrets NIV elicited HAI and MN responses exceeding those induced by IIV-HD against homologous A(H3N2) by 7 fold, A(H1N1) by 26 fold, and B strain viruses by 2 fold. NIV also induced MN responses against all historic A/H3N2 strains tested, spanning more than a decade of viral evolution from the 2000–2017 influenza seasons whereas IIV and IIV-HD induced HAI and MN responses were largely directed against the homologous A(H3N2), A(H1N1), and B virus strains. NIV induced superior protection compared to IIV and IIV-HD in ferrets challenged with a homologous or 10-year drifted influenza A(H3N2) strain. HAI positive and HAI negative neutralizing monoclonal antibodies derived from mice immunized with NIV were active against homologous and drifted influenza A(H3N2) strains. Taken together these observations suggest that NIV can induce responses to one or more highly conserved HA head and stem epitopes and result in highly neutralizing antibodies against both homologous and drift strains.     

Lack of neonatal Fc receptor does not diminish the efficacy of the HSV-1 0ΔNLS vaccine against ocular HSV-1 challenge

The neonatal Fc receptor (FcRn) is constitutively expressed in the cornea and is up-regulated in response to herpes simplex virus type 1 (HSV-1). Previously, we found targeting cornea FcRn expression by small interfering RNA-mediated knockdown reduced the local efficacy of HSV-1 0ΔNLS vaccinated C57BL/6 mice against ocular challenge with HSV-1. The current study was undertaken to evaluate the HSV-1 0ΔNLS vaccine efficacy in FcRn deficient (FcRn KO) mice challenged with HSV-1. Whereas there was little neutralizing antibody detected in the serum of HSV-1 0ΔNLS vaccinated FcRn KO mice, these mice exhibited the same degree of protection against ocular challenge with HSV-1 as wild type (WT) C57BL/6 mice as measured by cumulative survival, infectious virus shed or retained in tissue, and corneal pathology including opacity and neovascularization. Mock-vaccinated FcRn KO mice were found to be more sensitive to ocular HSV-1 infection compared to mock-vaccinated (WT) mice in terms of cumulative survival and virus shedding. In addition, the FcRn KO mice generated significantly fewer effector (CD3⁺CD44⁺CD62L^-) and central (CD3⁺CD44⁺CD62L⁺) memory CD8⁺ T cells compared to the WT mice 7 days post infection. Collectively, mock-vaccinated FcRn KO mice are susceptible to ocular HSV-1 infection but HSV-1 0ΔNLS vaccinated FcRn KO mice are resistant suggesting that in addition to the FcRn, other pathways are involved in mediating the protective effect of the HSV-1 0ΔNLS vaccine against subsequent HSV-1 challenge.     

Evaluation of a virosomal H5N1 vaccine formulated with Matrix M™ adjuvant in a phase I clinical trial

The avian influenza H5 virus epizootic continues to cause zoonosis with human fatalities, highlighting the continued need for pandemic preparedness against this subtype. This study evaluated the tolerability and immunogenicity of a Matrix M™ adjuvanted virosomal H5N1 vaccine in a phase I clinical trial. Sixty healthy adults were vaccinated intramuscularly with two doses of influenza H5N1 (NIBRG-14) virosomal vaccine alone (30 μg haemagglutinin (HA)) or 1.5, 7.5 or 30 μg HA formulated with 50 μg Matrix M™ adjuvant. The antibody response was analysed by haemagglutination inhibition (HI), microneutralisation (MN) and single radial haemolysis (SRH) assays. The vaccine was well tolerated in all groups but injection site pain was more frequently observed in the Matrix M™ adjuvanted groups. The vaccine elicited homologous and heterologous H5N1-specific antibody responses and the Matrix M™ adjuvanted formulations met all the EU regulatory criteria. In conclusion, Matrix M™ adjuvant was well tolerated and augmented the antibody response allowing considerable dose sparing down to 1.5 μg HA.     

Safety, immunogenicity and efficacy of modified vaccinia Ankara (MVA) against Dryvax challenge in vaccinia-naïve and vaccinia-immune individuals

Modified vaccinia Ankara (MVA) was evaluated as an alternative to Dryvax in vaccinia-na?ve and vaccinia-immune adult volunteers. Subjects received intramuscular MVA or placebo followed by Dryvax challenge at 3 months. Two or more doses of MVA prior to Dryvax reduced severity of lesion formation, decreased magnitude and duration of viral shedding, and augmented post-Dryvax vaccinia-specific CD8(+) T cell responses and extracellular enveloped virus protein-specific antibody responses. MVA vaccination is safe and immunogenic and improves the safety and immunogenicity of subsequent Dryvax vaccination supporting the potential for using MVA as a vaccine in the general population to improve immunity to orthopoxviruses.     

Utilizing computerized entertainment education in the development of decision aids for lower literate and naïve computer users

Decision aids have been developed by using various delivery methods, including interactive computer programs. Such programs, however, still rely heavily on written information, health and digital literacy, and reading ease. We describe an approach to overcome these potential barriers for low-literate, underserved populations by making design considerations for poor readers and na?ve computer users and by using concepts from entertainment education to engage the user and to contextualize the content for the user. The system design goals are to make the program both didactic and entertaining and the navigation and graphical user interface as simple as possible. One entertainment education strategy, the soap opera, is linked seamlessly to interactive learning modules to enhance the content of the soap opera episodes. The edutainment decision aid model (EDAM) guides developers through the design process. Although designing patient decision aids that are educational, entertaining, and targeted toward poor readers and those with limited computer skills is a complex task, it is a promising strategy for aiding this population. Entertainment education may be a highly effective approach to promoting informed decision making for patients with low health literacy.     

Safety and immunogenicity of an MF59®-adjuvanted A/H1N1 pandemic influenza vaccine in children from three to seventeen years of age

ObjectivesThis study was designed to identify the optimal dose of an MF59^®-adjuvanted, monovalent, A/H1N1 influenza vaccine in healthy paediatric subjects.MethodsSubjects aged 3–8 years (n = 194) and 9–17 years (n = 160) were randomized to receive two primary doses of A/H1N1 vaccine containing either 3.75 μg antigen with half a standard dose of MF59 adjuvant, 7.5 μg antigen with a full dose of MF59, or (children 3–8 years only), a non-adjuvanted 15 μg formulation. A booster dose of MF59-adjuvanted seasonal influenza vaccine including homologous A/H1N1 strain was given one year after priming. Immunogenicity was assessed by haemagglutination inhibition (HI) and microneutralization assays. Vaccine safety was assessed throughout the study (up to 18 months).ResultsA single priming dose of either MF59-adjuvanted formulation was sufficient to meet the European licensure criteria for pandemic influenza vaccines (HI titres ≥1:40 > 70%; seroconversion > 40%; and GMR > 2.5). Two non-adjuvanted vaccine doses were required to meet the same licensure criteria. After first and second doses, percentage of subjects with HI titres ≥1:40 were between 97% and 100% in the adjuvanted vaccine groups compared with 68% and 91% in the non-adjuvanted group, respectively. Postvaccination seroconversion rates ranged from 91% to 98% in adjuvanted groups and were 68% (first dose) and 98% (second dose) in the non-adjuvanted group. HI titres ≥1:330 after primary doses were achieved in 69% to 90% in adjuvanted groups compared with 41% in the non-adjuvanted group. Long-term antibody persistence after priming and a robust antibody response to booster immunization were observed in all vaccination groups. All A/H1N1 vaccine formulations were generally well tolerated. No vaccine-related serious adverse events occurred, and no subjects were withdrawn from the study due to an adverse event.ConclusionsAn MF59-adjuvanted influenza vaccine containing 3.75 μg of A/H1N1 antigen was well tolerated and sufficiently immunogenic to meet all the European licensure criteria after a single dose in healthy children 3–17 years old.     

Comparison of the immune responses to the CIA06-adjuvanted human papillomavirus L1 VLP vaccine with those against the licensed HPV vaccine Cervarix™ in mice

CIA05 is a toll-like receptor (TLR) 4 agonist derived from an Escherichia coli lipopolysaccharide (LPS) mutant and has been shown to have potential as a vaccine adjuvant. In this study, we investigated the immunopotentiating activity of the adjuvant system CIA06, which is comprised of CIA05 and aluminum hydroxide (alum), when used with the human papillomavirus (HPV) L1 virus-like particles (VLPs) vaccine. BALB/c mice were immunized intramuscularly three times at 2-week intervals with HPV16 L1 VLPs alone or in the presence of various combinations of CIA05 and alum, and the immune responses were assessed. We found that the combination of CIA05 and alum at a ratio of 1:50 (designated CIA06B) yielded the highest immune response in terms of serum anti-HPV L1 VLP IgG antibody titers, splenocyte interferon (IFN)-γ secretion, and antigen-specific memory B cell responses. The immunogenicity of the CIA06B-adjuvanted HPV16/18 L1 VLP vaccine was compared with that of the currently licensed HPV vaccine Cervarix™. The CIA06B-adjuvanted vaccine was similar to Cervarix™ with regard to eliciting serum antigen-specific IgG antibodies and virus-neutralizing antibodies but more effective at inducing splenic cytokine production and memory B cells. We also observed that the antigen-specific IgG antibody titers, splenic IFN-γ secretion and memory B cells induced by the CIA06B-adjuvanted HPV vaccine remained high up to 24 weeks post-immunization. Based on these data, we concluded that CIA06B may have potential as an adjuvant in a potent prophylactic vaccine against HPV infection.     

Safety and immunogenicity of an MF59(®)-adjuvanted A/H5N1 pre-pandemic influenza vaccine in adults and the elderly

Background

The potential consequences of an avian influenza pandemic warrants the development of safe, highly immunogenic pre-pandemic A/H5N1 vaccines with cross-clade protection. In this randomized, controlled study we compared the immunogenicity and safety of an MF59^®-adjuvanted (Novartis Vaccines, Marburg, Germany) A/H5N1 pre-pandemic vaccine with that of a licensed, MF59-adjuvanted, seasonal influenza vaccine.

Methods

Healthy adult (18–60 years, n = 3372) and elderly (≥61 years, n = 275) volunteers received either an initial dose of a licensed, non-adjuvanted, trivalent, seasonal influenza vaccine (Agrippal^®) on Day 1, followed by one dose of MF59-H5N1 study vaccine on Day 22 and a second dose of MF59-H5N1 on Day 43, or alternatively, placebo on Day 1 followed by one dose of MF59-adjuvanted seasonal reference vaccine on Day 22 and a second dose of reference vaccine on Day 43. Homologous and cross-reactive A/H5N1 antibody responses were analysed by haemagglutination inhibition (HI), single radial haemolysis (SRH), and microneutralization (MN) assays three weeks after each vaccination. Vaccine safety was assessed throughout the study.

Results

Analysis by HI assay found that two doses of MF59-H5N1 resulted in a seroconversion rate of 56% and a geometric mean ratio (GMR) of 7.1 in adult subjects. Similar results were observed on analysis by SRH (GMR 4.03; seroconversion 78% and seroprotection 91%) and MN (seroconversion 67%) assays. These data met the European licensure criteria for influenza vaccines. No significant difference in immunogenicity was detected between the adult and elderly populations. Anti-A/H5N1 cross-clade antibodies were detected by SRH, 49% of adult and 32% of elderly subjects achieved seroconversion after the second vaccine dose. Overall, MF59-H5N1 containing 7.5 μg antigen was less reactogenic than the MF59-adjuvanted trivalent seasonal vaccine which contained 15 μg antigen for each component strain.

Conclusions

Two doses of MF59-H5N1 vaccine were well tolerated and induced adequate levels of seroprotection against homologous and cross-clade A/H5N1 virus. These data support the suitability of MF59-adjuvanted A/H5N1 vaccine for pre-pandemic use in adults and the elderly.