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To achieve global herd immunity, widespread vaccination is the most effective strategy. Vaccines stimulate the immune system, generating cytokines and chemokines, isotype antibodies, and neutralizing antibodies; all these molecules collectively provide a more comprehensive characterization of the immune response post-vaccination. We conducted a longitudinal study in northwestern Mexico, involving 120 individuals before vaccination and after the first dose of the SARS-CoV-2 vaccine, and 46 individuals after their second dose. Our findings reveal that antibody levels stabilize over time; cytokine levels generally increase following the first dose but decrease after the second dose and higher than normal levels in IgG1 and IgG3 concentrations are present. Most of the innate cytokines determined in this study were higher after the first dose of the vaccine. Regardless of previous infection history, this finding suggests that the first dose of the vaccine is crucial and may stimulate immunity by enhancing the innate immune response. Conversely, increased levels of IL-4, indicative of a Th2 response, were found in individuals without prior exposure to the virus and in those vaccinated with CoronaVac. These results suggest that the immune response to COVID-19 vaccines is multi-faceted, with preexisting immunity potentiating a more robust innate response. Vaccine type plays a critical role, with genetic vaccines favoring a Th1 response and inactivated vaccines like CoronaVac skewing toward a Th2 profile.

Few papers focus their attention on VZV vaccination effectiveness among people living with HIV (PLWH). Flanking the live attenuated vaccine (VZL) available, a newly recombinant vaccine (RZV) was recently introduced and approved for HZ prevention among adults. PLWH represents a population on which a particular attention should be applied, in order to guarantee the vaccine efficacy and safety. We performed a literature search in USNLM, PubMed, PubMed Central, PMC and Cochrane Library. From all the publications found eligible, data were extracted and processed per population, vaccine type, immunogenicity and ADRs. The review of the 13 included studies shows that both RZV and VZL are immunogenic and have an acceptable safety profile in adults and children living with HIV. However, given the lack of research available about vaccine efficacy in preventing VZV and HZ in PLWH, additional studies need to be performed, in order to achieve a full completeness of data.

Influenza vaccination is the most cost-effective strategy for influenza prevention. Influenza vaccines have been found to be effective against symptomatic and medically attended outpatient influenza illnesses. However, there is currently a lack of data regarding the effectiveness of inactivated influenza vaccines in Chongqing, China. We conducted a prospective observational test-negative design study. Outpatient and emergency cases presenting with influenza-like illnesses (ILI) and available influenza reverse transcription polymerase chain reaction (RT-PCR) were selected and classified as cases (positive influenza RT-PCR) or controls (negative influenza RT-PCR). A total of 7,307 cases of influenza and 7,905 control subjects were included in this study. The overall adjusted influenza vaccine effectiveness (IVE) was 44.4% (95% confidence interval (CI): 32.5-54.2%). In the age groups of less than 6 years old, 6-18 years old, and 19-59 years old, the adjusted IVE were 32.2% (95% CI: 10.0-48.9%), 48.2% (95% CI: 30.6-61.4%), and 72.0% (95% CI: 43.6-86.1%). The adjusted IVE for H1N1, H3N2 and B (Victoria) were 71.1% (95% CI: 55.4-81.3%), 36.1% (95% CI: 14.6-52.2%) and 33.7% (95% CI: 14.6-48.5%). Influenza vaccination was effective in Chongqing from 2018 to 2022. Evaluating IVE in this area is feasible and should be conducted annually in the future.

The influenza viruses cause seasonal respiratory illness that affect millions of people globally every year. Prophylactic vaccines are the recommended method to prevent the breakout of influenza epidemics. One of the current commercial influenza vaccines consists of inactivated viruses that are selected months prior to the start of a new influenza season. In many seasons, the vaccine effectiveness (VE) of these vaccines can be relatively low. Therefore, there is an urgent need to develop an improved, more universal influenza vaccine (UIV) that can provide broad protection against various drifted strains in all age groups. To meet this need, the computationally optimized broadly reactive antigen (COBRA) methodology was developed to design a hemagglutinin (HA) molecule as a new influenza vaccine. In this study, COBRA HA-based inactivated influenza viruses (IIV) expressing the COBRA HA from H1 or H3 influenza viruses were developed and characterized for the elicitation of immediate and long-term protective immunity in both immunologically naïve or influenza pre-immune animal models. These results were compared to animals vaccinated with IIV vaccines expressing wild-type H1 or H3 HA proteins (WT-IIV). The COBRA-IIV elicited long-lasting broadly reactive antibodies that had hemagglutination-inhibition (HAI) activity against drifted influenza variants.

Mucosal immunity plays a crucial role in combating and controlling the spread of highly mutated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recombinant subunit vaccines have shown safety and efficacy in clinical trials, but further investigation is necessary to evaluate their feasibility as mucosal vaccines. This study developed a SARS-CoV-2 mucosal vaccine using spike (S) proteins from a prototype strain and the omicron variant, along with a cationic chitosan adjuvant, and systematically evaluated its immunogenicity after both primary and booster immunization in mice. Primary immunization through intraperitoneal and intranasal administration of the S protein elicited cross-reactive antibodies against prototype strains, as well as delta and omicron variants, with particularly strong effects observed after mucosal vaccination. In the context of booster immunization following primary immunization with inactivated vaccines, the omicron-based S protein mucosal vaccine resulted in a broader and more robust neutralizing antibody response in both serum and respiratory mucosa compared to the prototype vaccine, enhancing protection against different variants. These findings indicate that mucosal vaccination with the S protein has the potential to trigger a broader and stronger antibody response during primary and booster immunization, making it a promising strategy against respiratory pathogens.

The immune response to inactivated influenza vaccines (IIV) is influenced by multiple factors, including hemagglutinin content and egg-based manufacturing. Only two US-licensed vaccines are manufactured without egg passage: cell culture-based inactivated vaccine (ccIIV) and recombinant vaccine (RIV). We conducted a randomized open-label trial in central Wisconsin during the 2018-19 and 2019-20 seasons to compare immunogenicity of sequential vaccination. Participants 18-64 years old were randomized 1:1:1 to receive RIV, ccIIV or IIV in strata defined by number of influenza vaccine doses in the prior 3 years. They were revaccinated with the same product in year two. Paired serum samples were tested by hemagglutination inhibition against egg-adapted and cell-grown vaccine viruses. Serologic endpoints included geometric mean titer (GMT), mean fold rise, and percent seroconversion. There were 373 participants randomized and vaccinated in 2018-19; 332 were revaccinated in 2019-20. In 2018-19, RIV and ccIIV were not more immunogenic than IIV against A/H1N1. The post-vaccination GMT against the cell-grown 3C.2a A/H3N2 vaccine virus was higher for RIV vs IIV ( p  = .001) and RIV vs ccIIV ( p  = .001). The antibody response to influenza B viruses was similar across study arms. In 2019-20, GMT against the cell-grown 3C.3a A/H3N2 vaccine virus was higher for RIV vs IIV ( p  = .03) and for RIV vs ccIIV ( p  = .001). RIV revaccination generated significantly greater backboosting to the antigenically distinct 3C.2a A/H3N2 virus (2018-19 vaccine strain) compared to ccIIV or IIV. This study adds to the evidence that RIV elicits a superior immunologic response against A/H3N2 viruses compared to other licensed influenza vaccine products.

The world remains cautiously optimistic about a COVID-19 vaccine that is relatively safe and efficacious and that offers sufficient long-lasting protection/immunity by neutralizing the virus infectivity. However, key technical hurdles pertaining to antigen-adjuvant formulation, delivery, and manufacturing challenges of lipid nanoparticles (LNPs) for mRNA vaccines and stability of formulations need to be addressed for successful product development and stockpiling. In addition, the dosage form, the dosage level and regimen for eliciting a protective immune response remain to be established. The high dependence of global supply chains and demand-supply to sourcing quality raw materials, glassware and other supplies, along with the stress on existing production capacities and platform-specific manufacturing challenges could impede vaccine development and access. This article provides critical analysis of vaccine development processes and unit operations that can derail the pandemic response, and also extends to other emerging infectious disease development efforts - issues that take on added significance given the global mandate for an accelerated and at-risk development path to tackle the COVID-19 pandemic.

This study was planned to evaluate whether a 3-month treatment with Lactobacillus rhamnosus GG (LGG) can modify immune system functions in children and adolescents with type 1 diabetes (T1D), leading to an increased immune response to an injectable quadrivalent inactivated influenza vaccine (QIV). A total of 87 pediatric patients with T1D were screened, although 34 patients in the Probiotic group and 30 in the Control group accepted to be vaccinated with QIV and completed the study. Vaccine immunogenicity and safety and the inflammatory cytokine response were studied. Results showed that QIV was immunogenic and safe in T1D pediatric patients and pre-administration of LGG for three months did not substantially modify the QIV humoral immunity. The combination of QIV and LGG reduced inflammatory responses (i.e., IFN-γ, IL17A, IL-17F, IL-6, and TNF-α) from activated PBMCs of pediatric patients with T1D, without dampening the production of seroprotective antibodies. In conclusion, QIV is associated with an adequate immunogenicity in children and adolescents with T1D in presence of a good safety profile. Although a systematic administration of LGG did not result in an improvement of humoral responses to an influenza vaccine, the probiotic did induce important anti-inflammatory effects.

Seasonal influenza causes substantial morbidity and mortality in China, which largely results from limited vaccine accessibility and poor vaccination coverage. Since 2013, Sanofi Pasteur's facilities in Shenzhen, China have produced a trivalent inactivated influenza vaccine (Shz-IIV3) for each influenza season according to Chinese pharmacopeia requirements. However, the immunogenicity of Shz-IIV3 has not been compared to existing Chinese trivalent inactivated influenza vaccines (IIV3s). Here, we describe the results of a phase IV, observer-blind, randomized study to evaluate whether the immunogenicity of Shz-IIV3 was non-inferior to a comparator IIV3 (Hualan Biological Engineering Inc) also manufactured and licensed in China. Healthy adults aged 18-59 years were randomly assigned in a 1:1 ratio to receive a single 0.5-mL intramuscular injection of the 2017-2018 Northern Hemisphere formulation of Shz-IIV3 (n = 800) or the comparator IIV3 (n = 799). Between baseline and day 28 after vaccination, hemagglutination inhibition titers for the three vaccine strains increased by at least 4-fold and were of similar magnitude in Shz-IIV3 and comparator IIV3 recipients. The rate of seroconversion or significant increase in titers was 62% to 92% in Shz-IIV3 recipients, and 63% to 91% in comparator IIV3 recipients. Post-vaccination hemagglutination inhibition titers and seroconversion rates for Shz-IIV3 were statistically non-inferior to the comparator IIV3 for all three influenza vaccine strains. Rates of solicited and unsolicited vaccine-related adverse events were similar between the two vaccine groups. These results demonstrated that Shz-IIV3 was as immunogenic and safe in adults as a comparator Chinese IIV3, and support the continued use of Shz-IIV3 in China.

Background : Under the WHO's Global Action Plan for influenza vaccines, we conducted a phase 2-3 study of IVACFLU-S, a trivalent, seasonal inactivated influenza vaccine candidate. Methods : In the phase 2 portion of the study, 252 participants received one dose of 15 mcg hemagglutinin (HA) vaccine per strain or placebo. Following determination of safety, 636 additional participants were randomized in phase 3 to receive vaccine or placebo. Immunogenicity was assessed in a subset of the participants in the phase 3 study. Results : Higher proportion (70%) of participants in the IVACFLU-S arm reported solicited local adverse events (AEs) ( p < .0001) as compared to placebo (25%). Mild injection site pain and tenderness were most common AEs seen in 55% and 60% of participants in the vaccine group. The solicited systemic AEs were comparable ( p = .4149). The majority of solicited and unsolicited AEs were mild to moderate in severity. In the vaccine arm for the combined age group of 18-60 years of age, seroconversion against antigens A/H1N1, A/H3N2, and B was achieved in 70.3%, 76.1%, and 54.1% of participants respectively; seroprotection against antigens A/H1N1, A/H3N2, and B was achieved in 83.3%, 86.6%, and 60.3% of participants respectively; and the geometric mean fold rise for the hemagglutinin-inhibition (HI) antibody titers against antigen A/H1N1, A/H3N2, and B were 13.15, 11.85, and 5.87, respectively. Conclusion : This study demonstrates the local reactogenicity, other safety, and immunogenicity of IVACFLU-S, first domestically produced influenza vaccine in Vietnam. ClinicalTrials.gov number NCT03095599 (March 29, 2017).

Two antigenically distinct influenza B lineage viruses (Yamagata/Victoria) have been co-circulating globally since the mid-1980s. The quadrivalent influenza vaccine (QIV) may provide better protection against unpredictable B strains. We conducted a randomized, double-blind, phase III trial to evaluate the immunogenicity and safety of an egg-based inactivated, split-virion QIV (GC3110A). Subjects aged ≥ 19 years were randomized 2:1:1 to be vaccinated with QIV- GC3110A, trivalent influenza vaccine (TIV) containing the Yamagata lineage strain (TIV-Yamagata), or TIV containing the Victoria lineage strain (TIV-Victoria). Hemagglutination inhibition assays were performed 21 days post-vaccination. Solicited/unsolicited adverse events (AEs) were assessed within 21 days after vaccination, while serious AEs were reported up to six months after vaccination. A total of 1,299 were randomized to receive QIV-GC3110A (648 subjects), TIV-Yamagata (325 subjects), or TIV-Victoria (326 subjects). Compared to the TIVs, the QIV-GC3110A met the non-inferiority criteria for all four subtype/lineage strains with respect to the geometric mean titer (GMT) ratio and the difference of seroconversion rate. The safety profiles of QIV-GC3110A were consistent with those of TIV. In conclusion, QIV-GC3110A is safe, immunogenic, and comparable to strain-matched TIV.

Being vigilant of the potential for an influenza pandemic, the Global Action Plan for Influenza Vaccines (GAP) promoted the establishment and maintenance of local vaccine manufacturing capacity. In accordance with this, the Thai government has developed its national strategic plan for influenza pandemic preparedness including the plan for manufacturing influenza vaccine in Thailand. With the support of WHO, the Thai Government Pharmaceutical Organization (GPO) as the developed local production capacity of influenza vaccines. The H1N1 live attenuated influenza vaccine (LAIV) and H5N2 LAIV produced by GPO have been proven to be safe and immunogenic through clinical trials, followed by Thai FDA licensure for pandemic use. The GPO-produced H5N2 LAIV has been proven to have priming effects on an inactivated subunit H5N1 booster vaccine. This Thai local manufacturer is now expanding its capacity to Inactivated Influenza Vaccine (IIV), aiming for sustainable influenza vaccine production for national coverage.

Rabies is the most lethal zoonotic, vaccine-preventable viral disease in the world. Its treatment is complicated by insufficient vaccine supply and the requirement for four to five repeated injections, as commercially available inactivated rabies lack adjuvant and have low immunogenicity. In this study, we focused on the role of a Krebs cycle intermediate, succinate dehydrogenase (SDH), in the innate immune response to cytokine production. We formulated a novel nanoemulsion adjuvant, Golden03, which stabilizes mouse SDH activity and contains more coenzyme Q10 and succinic acid than the classic MF59 adjuvant. Mice were immunized on days 1, 3, and 7, with seroconversion rate results suggesting that Golden03 significantly enhanced vaccine-stimulated antibody production against the rabies virus. Neutralizing antibody concentration testing by RFFIT indicated that treatment with Golden03 could result in antibody levels of up to 0.74 IU/mL 5 days post infection (DPI). ELISPOT for IFN-γ in mouse spleen cells showed that Golden03 enhanced immune responses at 14 DPI, inducing a rapid and powerful cellular response compared to the control group. Furthermore, the Vaccine-Golden03 group displayed no obvious weight loss or death after intracranial injection with CVS-11. An additional advantage is that Golden03 allowed for a three-quarter reduction in dose, while maintaining its efficacy and rapid stimulation effect. We suggest that Golden03 could be developed as a potential adjuvant for use in human rabies vaccine.

Safety surveillance is required for each season's influenza vaccines to rapidly detect and evaluate potential new safety concerns before the peak period of immunization. Here we report the results of an enhanced passive safety surveillance for a trivalent split-virion inactivated influenza vaccine (IIV3; Vaxigrip®), an intradermal version of this vaccine (IIV3-ID; Intanza® 15 µg), and a recently licensed quadrivalent version (IIV4; VaxigripTetra TM ) during the 2017/18 influenza season in the UK and Republic of Ireland. The primary objective was to determine the rates of adverse reactions (ARs) occurring within 7 days following routine vaccination. Between September and November 2017, 979 safety report cards were distributed to vaccinees receiving IIV3-ID, 1005 to those receiving IIV3, and 957 to those receiving IIV4. At least one AR was reported by 28 participants (2.9%) vaccinated with IIV3-ID, 14 participants (1.4%) vaccinated with IIV3, and 20 participants (2.1%) vaccinated with IIV4. The most frequent ARs were injection-site reactions and headache. One participant vaccinated with IIV3-ID reported two suspected serious ARs (dyskinesia and a shock symptom), although these could not be confirmed as vaccine-related. Rates of ARs for IIV3 and IIV3-ID for 2017/18 did not differ from the 2016/17 rates. For IIV4, in its first season since licensure, AR frequencies were similar to those in the Summary of Product Characteristics. In conclusion, no change was found compared to the known or expected AR rates for IIV3, IIV3-ID, or IIV4 during the 2017/18 season.

A quadrivalent split-virion inactivated influenza vaccine (IIV4; Fluzone® Quadrivalent, Sanofi Pasteur) has been available in the US since 2013 for individuals aged ≥ 6 months. Here, we describe the results of an open-label, multicenter trial (WHO Universal Trial Number U1111-1143-8370) evaluating the immunogenicity and safety of IIV4 in Indian children aged 6-35 months and 3-8 years, adolescents aged 9-17 years, and adults aged ≥ 18 years (n = 100 per group). Post-vaccination hemagglutination inhibition titers for all strains in all age groups were ≥ 8 fold higher than at baseline (range, 8-51). At least 70% of participants in all age groups seroconverted or had a significant increase in titer for each strain. The most common solicited reactions were injection-site pain and tenderness, plus fever in participants 6-23 months and myalgia in older children and adolescents. All injection-site reactions and most systemic reactions were grade 1 or 2 and resolved within 3 days. Only three vaccine-related unsolicited adverse events were reported, all of which were grade 1 or 2 and transient. No immediate adverse events, adverse events leading to study discontinuation, adverse events of special interest, or serious adverse events were reported. This study showed that IIV4 was well tolerated and highly immunogenic in all age groups. This adds important data on the safety, tolerability, and immunogenicity of influenza vaccines in India.

The Dominican Republic, historically non-endemic for cholera, is experiencing an ongoing cholera epidemic. We assessed the safety and immunogenicity of two doses of the killed bivalent (O1 and O139) whole-cell oral cholera vaccine (OCV) on day (D)0 and D14 in healthy participants aged ≥1 year. Immediate unsolicited systemic adverse events (AEs) were monitored up to 30 minutes and solicited systemic reactions, up to 7 days after each vaccination. Unsolicited AEs were recorded up to D14 (post-dose 1) and 30 days post-dose 2. A vibriocidal antibody assay with microtiter technique was used to measure serum antibodies to V. cholerae strains (O1 El Tor Inaba, O1 El Tor Ogawa, O139) on D0, D14 and D28. Geometric mean titers (GMTs) and seroconversion (≥4-fold increase from D0) rates were calculated. We recruited 336 participants; 112 in three age groups (1-4, 5-14 and ≥15 years). No safety concerns were observed. GMTs increased from baseline for all serotypes, with marked increases for O1 Inaba and Ogawa post-dose 1. Post-dose 2 GMTs tended to be equal or slightly lower, with ranges: O1 Inaba, 283 (95% confidence interval 191-419) to 612 (426-880); O1 Ogawa, 346 (223-536) to 754 (553-1028); and O139, 20.3 (13.5-30.6) to 43.8 (30.1-63.7). Seroconversion rates post-dose 2 for O1 Inaba and Ogawa were high (≥87%) for all age groups. OCV demonstrated an acceptable safety profile and robust immunogenicity in these participants, in-line with previous observations in epidemic and endemic settings.This study is registered on www.clinicaltrials.gov (NCT02434822).

Unlike the current injectable influenza vaccines, intranasally administered influenza vaccines induce influenza virus-specific IgA antibodies in the local respiratory mucosa as well as IgG antibodies in the systemic circulation. Our previous study showed that after five volunteers underwent intranasal administration with inactivated H3N2 or H5N1 vaccines, their IgA antibodies on the upper respiratory tract were present as monomers, dimers, and multimers (trimers and tetramers). Moreover, the multimers associated with the highest virus neutralizing activity. However, it has remained elusive whether a more practical intranasal vaccination strategy could induce the high-performance IgA multimers in the nasal mucosa. In the present study, volunteers were administered with two doses of the intranasal trivalent whole-virus inactivated influenza vaccine and showed that in nasal wash samples the amount of multimeric IgA correlated positively with virus neutralizing titers, indicating that the multimeric IgA antibodies play an important role in the antiviral activity at the nasal mucosa. Surface plasmon resonance analysis of the binding dynamics of nasal wash derived IgA monomers, dimers, and multimers against recombinant trimeric influenza virus HA showed that sample fractions containing IgA multimers dissociated from HA less well than sample fractions without IgA multimers. Thus, IgA multimers may "stick" to the antigen more tightly than the other structures. In summary, intranasal administration of two doses of multivalent inactivated influenza vaccines induced multimeric IgA. Multimerization of mucosal IgA antibodies conferred higher neutralizing activity against viruses in the nasal mucosa, possibly by increasing their cohesion to virus antigens.

The longevity of antibodies induced by inactivated enterovirus 71 type (EV71) vaccine is not well studied. To estimate the immunity persistence following two-dose vaccination of EV71 vaccine, a five-year follow-up study was conducted as an extension of a Phase III clinical trial. In this study, a sub-cohort of volunteers who was eligible for enrollment and randomly administrated either 2 dose EV71 vaccine or placebo in the phase III clinical trial was selected, and then further observed 64 months post the 1st vaccination. 211 Subjects (106 vaccine subjects and 105 placebo subjects) who provided a full series of blood samples (at all the sampling points) were included in the final analyzed population. Seropositive rate (SR) and geometric mean titer (GMT) of the neutralizing antibodies (NAb) was calculated to detect the dynamic profiles of EV71 vaccine-induced immunogenicity. SR at the 5th year remained 94.34% in the vaccine subjects, with a GMT of 141.42. The SR was 71.43% in the placebo subjects, with a GMT of 71.83. Despite natural infection consistently promoted the NAb increase in the placebo subjects, the SR and GMT in vaccine subjects remained significantly higher than that in the placebo subjects at all the sampling points. The inactivated EV71 vaccine-induced immunity had a good persistence, within 5 years following the primary vaccination.

This phase II / III clinical trial was conducted to evaluate the immunogenicity and safety of the Tetravalent Influenza vaccine (Split virion) I.P. (TetIV) developed indigenously in the country for the first time by M/s Cadila Healthcare Limited, India containing two influenza A and two influenza B strains, one of each, Yamagata (B/Phuket) and Victoria (B/Brisbane) lineage and also compare it to that of an licensed seasonal Trivalent Influenza vaccine (TriIV) of Sanofi Pasteur India Private Limited, containing the two influenza A and only the Yamagata lineage (B/Phuket) strain. Three hundred and fifty subjects of either sex, aged more than 18 years of age, were randomized in a 1:1 ratio to receive either the TetIV or TriIV. Immunogenicity assessments (antibody against A/H1N1, A/H3N2, B/Phuket and B/Brisbane) were done by Haemagglutination Inhibition assay at baseline and 21 d after vaccination. Solicited (local and systemic) and unsolicited adverse events were recorded for up to 42 d following vaccination. The TetIV was found to fulfill the criteria set by the European and the US regulatory authorities and WHO guidance on the requirements of clinical data for licensure of seasonal inactivated influenza vaccines. The seroconversion rates with TetIV were 93.5% for A/H1N1, 90.0% for A/H3N2, 70.0% for B/Phuket and 82.9% for B/Brisbane strain. There was no significant difference in the seroconversion and seroprotection rates at day 21 for A/H1N1, A/H3N2 and B/Phuket in the two groups while the TetIV was superior to the TrivIV for the seroconversion and the seroprotection rate for the B/Brisbane strain (Victoria lineage). Both the vaccines were well tolerated by all the study participants; addition of the fourth strain in the TetIV did not compromise the safety as compared to TriIV. The most common systemic adverse event reported in both the groups was headache followed by fever.

Neutralizing antibodies (NTAbs) is a major criterion for evaluation the immunogenicity of many vaccines, for example, poliovirus and EV71 vaccine. Here, we firstly discovered that polyclonal antibodies induced by inactivated CVA16 vaccine and lived CVA16 virus have poor ability to neutralize circulating CVA16 strains in vitro. However, the passive transfer of poorly neutralizing polyclonal antibodies can protect suckling mice from lethally challenged with circulating strains in vivo. In addition, the obvious dose response was found between the titer of antibodies and the survival rate. Interestingly, poorly neutralizing polyclonal antibodies against circulating CVA16 strains, have good ability to neutralize prototype strain G10 in vitro. Between G10 and circulating CVA16 strains, there are total 47 variant sites in capsid, which are near the interface of VP1, VP2, and VP3, and close to 2-fold axis. Based on the structure of CVA16, the obvious structural changes were observed in residue 213 of VP1 GH loop, residue 139 of VP2 EF loop, and residues 59, 182 and 183 of VP3 GH loop. What we found may provide a new sight for the development of CVA16 vaccine.

The present incidence of leptospirosis in China is significantly lower than past rates, although small localized outbreaks continue to occur in epidemic regions. Improvements in sanitation, as well as vaccination of high-risk populations, have played crucial roles in reducing the disease burden. Several types of human leptospirosis vaccines have been developed, including inactivated whole-cell, outer-envelope, and recombinant vaccines. Of these, only a multivalent inactivated leptospirosis vaccine is available in China, which was added to the Chinese Expanded Program on Immunization in 2007. However, this vaccine elicits serogroup-specific immunity, and serogroup epidemiology should continue to be monitored to enhance vaccine coverage and distribution. On the other hand, the efficiency of the inactivated vaccine should be further improved by optimizing the formulation, and by expanding the target population. More importantly, additional investments should be made to develop universal recombinant vaccines.

Inactivated mouse-brain-derived Japanese encephalitis vaccine has a worrisome safety profile and the live attenuated vaccine is unsuitable in immunodeficiency. This study aimed to evaluate the immunogenicity and safety of an inactivated chromatographically purified Vero-cell-derived JE vaccine (CVI-JE, Beijing P-3 strain) in children. 152 healthy Thai children, with an average (SD) age of 14.4 (3.8) months, received 3 doses of CVI-JE on days 0, 7-28, and one year. Homologous JE neutralizing antibody titers (NT) were measured. All subjects had seroprotection [geometric mean titer (GMT) 150] 28 days' post 2nd vaccination. The seroprotection rates at 1 year after primary series and and 1 month after the booster were 89.3% (GMT 49) and 100% (GMT 621), respectively. Local and systemic reactions-fever (17.6%), vomiting (8%), and poor appetite (5.3%)-were noted within 28 days' post-vaccination. All these symptoms were self-limited., Conclusions: CVI-JE is safe, immunogenic, and provided high NT.

The search for a test that can predict vaccine efficacy is an important part of any vaccine development program. Although regulators hesitate to acknowledge any test as a true 'correlate of protection', there are many precedents for defining 'surrogate' assays. Surrogates can be powerful tools for vaccine optimization, licensure, comparisons between products and development of improved products. When such tests achieve 'reference' status however, they can inadvertently become barriers to new technologies that do not work the same way as existing vaccines. This is particularly true when these tests are based upon circularly-defined 'reference' or, even worse, proprietary reagents. The situation with inactivated influenza vaccines is a good example of this phenomenon. The most frequently used tests to define vaccine-induced immunity are all serologic assays: hemagglutination inhibition (HI), single radial hemolysis (SRH) and microneutralization (MN). The first two, and particularly the HI assay, have achieved reference status and criteria have been established in many jurisdictions for their use in licensing new vaccines and to compare the performance of different vaccines. However, all of these assays are based on biological reagents that are notoriously difficult to standardize and can vary substantially by geography, by chance (i.e. developing reagents in eggs that may not antigenitically match wild-type viruses) and by intention (ie: choosing reagents that yield the most favorable results). This review describes attempts to standardize these assays to improve their performance as surrogates, the dangers of over-reliance on 'reference' serologic assays, the ways that manufacturers can exploit the existing regulatory framework to make their products 'look good' and the implications of this long-established system for the introduction of novel influenza vaccines.

Influenza is a common disease and in children it can be severe enough to lead to hospitalization and death. Protection of all children against influenza, particularly the youngest, is strongly recommended by most health authorities. However, available vaccines cannot be used in the first 6 months of age, a period of life characterized by the highest risk of influenza-related complications. Maternal immunization is an attractive possibility to overcome this problem. For years, protection against influenza has been pursued by administering the trivalent inactivated vaccine given intramuscularly (IIV3). More recently, a trivalent live attenuated influenza vaccine (LAIV3) administered intranasally was licensed and adopted in a number of countries as an alternative to IIV3. In recent years, to increase protection and include a second B strain, quadrivalent inactivated (IIV4) and live attenuated vaccines (LAIV4) were prepared and licensed. However, during the 2015-2016 season the effectiveness of LAIVs was debated, and they were withdrawn from the list of recommended influenza vaccines in the USA. This review presents an update on the evidence related to the protection of infants against influenza through maternal immunization and the effectiveness of LAIV. Available data indicates that despite maternal immunization, a number of children have no protective antibody levels at birth, and in the majority of children with antibody protection, it is limited to the first 8 weeks of the postnatal period. Moreover, data on LAIV effectiveness in the pediatric population must be clarified because this vaccine can significantly improve vaccination coverage in children.

Here, we report a randomized multicenter phase III trial assessing the lot-to-lot consistency of the 2014-2015 Northern Hemisphere quadrivalent split-virion inactivated influenza vaccine (IIV4; Sanofi Pasteur) and comparing its immunogenicity and safety with that of trivalent inactivated influenza vaccine (IIV3) in younger and older adults (EudraCT no. 2014-000785-21). Younger (18-60 y, n = 1114) and older (>60 y, n = 1111) adults were randomized 2:2:2:1:1 to receive a single dose of one of three lots of IIV4, the licensed IIV3 containing the B Yamagata lineage strain, or an investigational IIV3 containing the B Victoria lineage strain. Post-vaccination (day 21) hemagglutination inhibition antibody titers were equivalent for the three IIV4 lots. For the pooled IIV4s vs. IIV3, hemagglutination inhibition antibody titers were also non-inferior for the A strains, non-inferior for the B strain when present in the comparator IIV3, and superior for the B strain lineage when absent from the comparator IIV3. For all vaccine strains, seroprotection rates were ≥98% in younger adults and ≥90% in older adults. IIV4 also increased seroneutralizing antibody titers against all three vaccine strains of influenza. All vaccines were well tolerated, with no safety concerns identified. Solicited injection-site reactions were similar for IIV4 and IIV3 and mostly grade 1 and transient. This study showed that in younger and older adults, IIV4 had a similar safety profile as the licensed IIV3 and that including a second B strain lineage in IIV4 provided superior immunogenicity for the added B strain without affecting the immunogenicity of the three IIV3 strains.

An inactivated split-virion quadrivalent influenza vaccine (IIV4; Fluzone® Quadrivalent; Sanofi Pasteur) has been available in the US since 2013 and in the Southern Hemisphere since 2015. Here, we describe the results of an open-label, post-licensure trial (WHO Universal Trial Number, U1111-1143-9256) to confirm the immunogenicity and safety of the Southern Hemisphere 2015 formulation of IIV4. Adults 18-60 years of age and > 60 years of age (n = 60 per age group) received a single 0.5-mL intramuscular injection of IIV4. After vaccination, hemagglutination inhibition titers for each strain in IIV4 increased by a geometric mean of at least 10-fold for younger adults and at least 9-fold for older adults. All of the younger adult participants and 98%-100% of the older adult participants had seroprotective titers for each strain. Also, at least 80% of younger adults and 78% of older adults seroconverted or had a significant increase in titer for all four vaccine strains. These post-vaccination immune responses exceeded the criteria of the Committee for Human Medicinal Products former Note for Guidance for influenza vaccines. Finally, no serious adverse events were reported, and no new safety signals were detected. These results confirmed that the Southern Hemisphere 2015 formulation of IIV4 was well tolerated, highly immunogenic, and met the criteria for influenza vaccine immunogenicity and safety.

VaxigripTetra® (Sanofi Pasteur, Lyon, France) is a quadrivalent split-virion inactivated influenza vaccine (IIV4) containing two B-lineage strains approved in the European Union and Taiwan in 2016 for individuals ≥ 3 years of age. Here, we describe an observer-blind, randomized, controlled, multicenter trial study evaluating the immunogenicity and safety of the Northern Hemisphere 2015-2016 formulations of IIV4 and the licensed split-virion trivalent inactivated influenza vaccine (IIV3) in the Republic of Korea (ClinicalTrials.gov no. NCT02550197). The study included 300 Korean adults 18-60 years of age randomized 2:1 to receive a single injection of IIV4 or IIV3. For each of the four vaccine strains in IIV4, 21 days after vaccination, geometric mean post-/pre-vaccination ratios of hemagglutination inhibition titers were ≥ 3.97. Seroconversion/significant increases rates were ≥ 40% for all but the A/H1N1 strain, for which the rate was 39.7%. Results were similar for the three strains in IIV3. For the additional B-lineage strain not in IIV3 (Victoria), hemagglutination inhibition antibody titers were higher for IIV4 than for IIV3. Solicited reactions and adverse events were similar between IIV4 and IIV3, and no serious adverse events or new safety signals were detected. These results confirm the robust immunogenicity and acceptable safety of IIV4 in adults 18-60 years of age and show that including a second B-lineage strain should provide broader protection against B-strain influenza without affecting vaccine safety or the immunogenicity of other three vaccine strains.

This study was a phase I double-blind, randomized, placebo-controlled trial to evaluate the safety and immunogenicity of a Serbian-produced seasonal trivalent split, inactivated influenza vaccine in healthy adults. The vaccine was manufactured in eggs by the Torlak Institute of Virology, Vaccines and Sera, Belgrade, Serbia and contained A/H1N1, A/H3N2 and B viruses. The clinical trial took place at the Clinical Center of Serbia in Belgrade. Sixty healthy volunteers, aged 18-45 years, were enrolled in the trial. On the day of immunization, volunteers were randomly assigned to receive either a single dose of the trivalent seasonal influenza vaccine (15 μg of hemagglutinin per strain) or placebo (phosphate-buffered saline). Subjects were monitored for adverse events through a clinical history and physical examination, and blood was taken for testing at screening and on day 8 to assess vaccine safety. Serum samples obtained before and 21 days after immunization were tested for influenza antibody titers using hemagglutination-inhibition (HAI) and microneutralization (MN) tests. No serious adverse events were reported. Pain and tenderness at the injection site were the most commonly reported symptoms in both vaccine and placebo groups. Overall, serum HAI responses of fourfold or greater magnitude were observed to H1, H3, and B antigen in 80%, 75%, and 70% of subjects, respectively. Seroprotection rates as measured by HAI were also high (100%, 100% and 86.67%, respectively, for H1, H3 and B). Thus, Torlak's seasonal trivalent influenza vaccine was not associated with adverse events, was well-tolerated and immunogenic. It should be further evaluated in clinical trials to provide sufficient safety and immunogenicity data for licensing in Serbia.

Background: The study was aimed at comparative evaluation of seasonal influenza vaccine RIBSP versus commercial vaccine VAXIGRIP® for immunogenicity and safety in the course of clinical trial phase II on healthy volunteers aged 18-60 years., Methods: The trial involved 150 subjects in randomized 2:1 groups that received either RIBSP vaccine or comparator vaccine VAXIGRIP®. One dose (0.5 ml) of either vaccine contained 15 μg of hemagglutinin of each influenza virus strain recommended by WHO for the Northern hemisphere in 2016-2017 flu season. The observation period lasted 21 day. The trial was registered at ClinicalTrials.gov identifier NCT 03016143., Results: Assessment of immunogenic activity of the vaccine under study showed that in 21 day the portion of participants with 4-fold seroconversions was 87.0% to A/H1N1; 63.0% to A/H3N2 and 59.0% to B virus. Antibody titer increase factor in the group of subjects that received RIBSP vaccine was 23.3 for A/H1N1; 4.4 for A/H3N2 and 4.5 for B virus. The volunteers that received RIBSP vaccine demonstrated 95% seroprotection level against A/H1N1; 84% against A/H3N2 and 80% against B virus. RIBSP vaccine met the CHMP criteria of the Committee for Medicinal Products for Human Use (CPMP/BWP/214/96). In the course of evaluating the vaccine safety no serious undesirable effects were recorded. All changes of laboratory data were slight and single in most cases. All recorded local reactions have been light in character and these have been predicted reactions observed at vaccination against influenza., Conclusion: Comparison of the allantoic inactivated split vaccine obtained in vaccines RIBSP and VAXIGRIP®, showed similar immunogenic activity. Both vaccines were safe for the study participants.

Since 2003 (US) and 2012 (Europe) the live attenuated influenza vaccine (LAIV) has been used as an alternative to the traditional inactivated influenza vaccines (IIV). The immune responses elicted by LAIV mimic natural infection and have been found to provide broader clinical protection in children compared to the IIVs. However, our knowledge of the detailed immunological mechanisims induced by LAIV remain to be fully elucidated, and despite 14 years on the global market, there exists no correlate of protection. Recently, matters are further complicated by differing efficacy data from the US and Europe which are not understood. Better understanding of the immune responses after LAIV may aid in achieving the ultimate goal of a future "universal influenza vaccine". In this review we aim to cover the current understanding of the immune responses induced after LAIV.

Influenza virus is a common pathogen implicated in respiratory tract infections, annually affecting up to 20% of the general population, and pneumonia is a leading cause of death after influenza infection. Post-influenza pneumonia is especially common in the elderly and chronically ill patients. The risk of post-influenza pneumonia is significantly increased according to the number of concurrent comorbidities. Vaccination is the primary measure used to abate influenza epidemics and associated complications. In meta-analyses, influenza vaccine significantly reduces pneumonia- and influenza-related hospitalizations, with a vaccine effectiveness of 25-53%. However, considering the poor effectiveness of conventional influenza vaccines in the elderly, several highly immunogenic influenza vaccines have been developed. Further evaluations of the comparative effectiveness of diverse vaccine formulations are warranted to assess their utility for preventing influenza infection, post-influenza pneumonia, and related hospitalization/mortality. Based on cost-effectiveness and budget impact analysis, influenza vaccination strategies should be tailored in the elderly.

The safety of vaccines is a critical factor in maintaining public trust in national vaccination programs. Vaccines are recommended for children, adults and elderly subjects and have to meet higher safety standards, since they are administered to healthy subjects, mainly healthy children. Although vaccines are strictly monitored before authorization, the possibility of adverse events and/or rare adverse events cannot be totally eliminated. Two main types of influenza vaccines are currently available: parenteral inactivated influenza vaccines and intranasal live attenuated vaccines. Both display a good safety profile in adults and children. However, they can cause adverse events and/or rare adverse events, some of which are more prevalent in children, while others with a higher prevalence in adults. The aim of this review is to provide an overview of influenza vaccine safety according to target groups, vaccine types and production methods.

Background: Leprosy is an infectious disease caused by the bacterium Mycobacterium leprae. Influenza vaccine is an important influenza prevention strategy and the preparations used display good safety and tolerability profiles. But the safety of applying influenza vaccine on the clinical cured leprosy patients is unclear., Methods: We conducted an observational clinical study, in Wuhan between November 15, 2016 and March 1, 2017. Two groups of participants ≥50 years of age received a 0.5 ml dose of the inactivated split-virion trivalent influenza vaccine and a follow-up 28 days observation of any solicited and unsolicited adverse events., Results: A total of 134 subjects were included in the study. The total rate of reactogenicity was 5.4% [2/37] in leprosy group and 15.5% [15/ 97] in control group, the difference of reactogenicity between two groups was not significant (p = 0.1522). For solicited injection-sites adverse events (AEs), 12.4% [12/ 97] participants in the control group reported of itching, pain, erythema, swelling or induration, and no participants in leprosy group reported of any solicited injection-sites AEs. For solicited systemic AEs, 7.2% [7 / 97] participants in the control group reported of fever, malaise or headache, and 2.7% [1 / 37] participants in the leprosy group reported of fever, statistic result showed that the difference was not significant (p = 0.4438). Unsolicited AEs was reported by one male aged 76, 4 hours after vaccination administration, his plantar ulcer area began bleeding. All AEs were grade 1 or grade 2, and no recurrence of lepra reaction, AEs leading to early withdrawal from the study, or deaths were reported in this study., Conclusions: To our knowledge, the present study is the first clinical study to evaluate the safety of influenza vaccine in clinically cured leprosy patients. We concluded that clinically cured leprosy patients are relatively safe for influenza vaccine. More importantly, our study make a positive and scientific efforts to eradicate discrimination on leprosy. In our study, we described a patient with plantar ulcer undergoing bleeding for 4 hours after vaccine administration. Based on evidence we have, we interpret that this adverse event may probably associated with vaccine, and patients with ulcer and leprosy need intensive attention after vaccines administration.

Young infants contribute to relatively high burden of vaccine-preventable diseases, including infections by influenza virus and Bordetella pertussis. Vaccination of pregnant women can enhance transplacental transfer of protective antibody to the fetus and protect the infant against disease during the first few months of life. Pregnant women are a priority group for seasonal influenza vaccination, due to third-trimester pregnancy being a risk-factor for severe influenza illness. Furthermore, randomized controlled trials confirmed that influenza vaccination during pregnancy confers protection against influenza-confirmed illness in the women, and their infants up to 3 months of age; and is also associated with 20% reduction in all-cause pneumonia among young-infants. Maternal influenza vaccination might also reduce the risk of low-birth weight, preterm births, and stillbirths however, data on this is conflicting. Vaccination of pregnant women with acellular pertussis vaccines reduces pertussis in their young infants by up to 93%. The increase in specific pertussis antibody among the infants born to vaccinated women might, however, interfere with the active pertussis vaccination of the infant following the primary series of vaccines. The clinical implication of this is yet to be ascertained, particularly since immune responses following the booster vaccine are unaffected. Vaccination of pregnant women with inactivated influenza vaccine and acellular pertussis vaccine have been demonstrated to confer protection to their young infants, and warrants consideration for inclusion into public health immunization programs, including in low and middle income countries.

Pertussis is a highly contagious respiratory disease caused by Bordetella pertussis. However, after the introduction of the whole-cell pertussis vaccine (wP), the annual incidence rates of the disease progressively declined. Despite this result, the inclusion of wP in the national immunization schedule of infants and young children was debated regarding its safety. Several efforts to produce vaccines based on B. pertussis components capable of evoking protective immunity with no or limited adverse events were made. Of these others, five pertussis antigens were considered possible components of acellular vaccines (aPs): pertussis toxin (PT), filamentous haemagglutinin (FHA), pertactin (PRN) and fimbria proteins 2 and 3. However, the introduction of aPs was followed by a slight but progressive increase in the incidence of pertussis. This paper discusses the potential reasons for reduced aPs efficacy. Moreover, it attempts to evaluate the real effectiveness of aPs and the potential differences between available preparations. Data analysis showed that several boosters are needed to maintain protection against pertussis and additional studies are needed to confirm the antigens that should be included in aPs to improve the prevention of pertussis.

An inactivated split-virion trivalent influenza vaccine (IIV3; Vaxigrip®, Sanofi Pasteur) has been available globally since 1968. Here, we describe the results of an open-label, post-licensure trial (EudraCT no. 2014-005078-12) to confirm the immunogenicity and safety of the Southern Hemisphere 2015 formulation of IIV3. Adults 18-60 years of age and > 60 years of age (60 per age group) received a single 0.5-ml intramuscular injection of IIV3. Between baseline and day 21 after vaccination, hemagglutination inhibition (HAI) titers for each strain in IIV3 increased, on average, by at least 11-fold for younger adults and at least 5-fold for older adults. After vaccination, 89%-100% of the younger adult participants and 90%-98% of the older adult participants attained seroprotection (HAI titer ≥ 40) for each strain. Also, 66%-81% of younger adults and 45%-63% of older adults seroconverted or had a significant increase in HAI titer for each strain. For both age groups, these post-vaccination immune responses exceeded the criteria of the Committee for Human Medicinal Products former Note for Guidance for influenza vaccines. No serious adverse events were reported, and no new safety signals were detected. In conclusion, this study confirmed that the Southern Hemisphere 2015 formulation of IIV3 was well tolerated, highly immunogenic, and met the criteria for influenza vaccine efficacy and safety.

This monocenter, descriptive, prospective, non-interventional study evaluated the long-term immune responses following routine vaccination with one or 2 doses of a licensed inactivated hepatitis A (HA) vaccine (Avaxim® 80U Pediatric) at age 11-23 months in a cohort of children from Mendoza, Argentina. Antibodies to hepatitis A virus (anti-HAV) were quantified annually up to Y5, and at Y7. Children whose titer decreased to below the seroprotection threshold (defined as an anti-HAV antibody concentration of ≥ 10 mIU/mL in a microparticle enzyme immunoassay up to Y5, or ≥ 3 mIU/mL in an electrochemiluminescence immunoassay at Y7) received a routine booster dose of the same HA vaccine. This report summarizes the data at 7 year after the first vaccination. Of 546 participants initially included, 264 participants remained at Y7 and provided blood samples. Of these, 204 having received one HA primary dose as a toddler were still seroprotected at Y7; titers for a further 7 also having received one HA dose as a toddler fell to below the seroprotection threshold and they therefore received a booster; all 53 having received 2 HA doses as a toddler and still present at Y7 remained seroprotected at Y7. One or 2 primary doses of this HA vaccine in toddlers result in very good persistence of anti-HAV up to 7 year post-first vaccination.

Influenza vaccination is considered the best mean for preventing the higher rates of mortality associated with influenza virus infection in the elderly as compared with younger people. Since the number of very elderly subjects, aged >85 years, is rapidly increasing, and some authors reported increments in influenza-associated mortality with age, the aim of this study was to increase the limited information available on the immunogenicity of the influenza vaccines in this age group. This was a retrospective study which analyzed the antibody response induced by commercially available trivalent inactivated influenza vaccines in 1491 elderly subjects (60-85 years old) and 1139 very elderly subjects (>85 years old) during 21 winter seasons included between 1993-1994 and 2014-2015. The antibody response of the two age groups was, in most instances, acceptable according to the Committee for Medical Products for Human Use and comparable. In accordance with previous data obtained in the elderly, the use of MF59-adjuvanted or intradermal administered vaccines (enhanced vaccines) was found to be preferable as compared with conventional formulations (split or subunit vaccines). Vaccines containing new strains induced higher antibody response as compared with vaccines with the same antigenic composition of the previous years. These results suggest that the current recommendation for use of enhanced influenza vaccines for the elderly is appropriate, but that efforts to improve the effectiveness of the present prophylactic measures against influenza are needed, especially in the years with vaccines with the same antigenic composition of the previous winter season.

The killed bivalent (O1 and O139) whole cell oral cholera vaccine (OCV) (Shanchol™) was first licensed in India in 2009 and World Health Organization pre-qualified in 2011. We assessed the safety and immunogenicity of this OCV in the Philippines. This was a phase IV, single-arm, descriptive, open-label study. We recruited 336 participants from 2 centers: 112 participants in each age group (1-4, 5-14 and ≥ 15 years). Participants received 2 OCV doses 14 d apart. Safety was monitored throughout the trial. Blood samples were collected at baseline (pre-vaccination) and 14 d after each dose. Serum vibriocidal antibody titers to V. cholerae O1 (El Tor Inaba and El Tor Ogawa) and O139 strains were assessed, with seroconversion defined as ≥ 4-fold increase from baseline in titers. No immediate unsolicited systemic adverse events/reactions were observed. Unsolicited systemic adverse events were mostly grade 1 intensity. One serious adverse event occurred after the first dose, but was unrelated to vaccination. High seroconversion rates (range 69-92%) were achieved against the O1 serotypes with a trend toward higher rates in the 1-4 y (86-92%) and 5-14 y (86-88%) age groups than the ≥ 15 y age group (69-83%). Lower seroconversion rates were achieved against the O139 serotype (35-70%), particularly in those aged ≥ 15 y (35-42%). The 2-dose regimen of the killed bivalent whole cell OCV was well-tolerated in this study conducted in the Philippines, a cholera-endemic country. Robust immune responses were observed even after a single-dose.

Frequent mismatches between the predominant circulating B strain lineage and the B strain lineage in trivalent influenza vaccines have resulted in missed opportunities to prevent influenza illness. Quadrivalent influenza vaccines containing B strains from each of the 2 lineages have been developed for improved prevention of influenza B infections. Here, we describe the results of a phase III, randomized, double-blind, active-controlled, multicenter trial examining the safety and immunogenicity of a split-virion inactivated quadrivalent influenza vaccine (IIV4) in 675 adults ≥ 65 y of age (NCT01218646). Participants were randomly assigned 1:1:1 to receive a single intramuscular injection with the investigational IIV4, or one of 2 split-virion trivalent inactivated influenza vaccines (IIV3s): a licensed IIV3 containing a B Victoria-lineage strain or an investigational IIV3 containing a B Yamagata-lineage strain. Post-vaccination (day 21) hemagglutinin inhibition titers to all strains induced by IIV4 were statistically non-inferior to those induced by the 2 IIV3s. In addition, for each B strain, rates of seroconversion in the IIV4 group were superior to those induced by the comparator IIV3 not containing that B strain. For all vaccines, the most common solicited reaction was injection-site pain, and most reactions were mild to moderate in intensity and transient. Overall safety profiles were similar between IIV4 and the IIV3s, and no vaccine-related serious adverse events were reported. These results confirm that in adults ≥ 65 y of age, IIV4 was well tolerated and immunogenic against the additional B lineage strain without compromising the immunogenicity of the other 3 vaccine strains.

Background: Vitamin D is an immunomodulating hormone, which has been associated with susceptibility to infectious diseases., Methods: Serum vitamin D levels in 135 children ages 3-17 y were measured at baseline and hemagglutinin influenza antibody titers were measured pre- and 21 d post influenza vaccination with live attenuated influenza vaccine (LAIV) or inactivated influenza vaccine (IIV). Height and weight were derived from the electronic medical record and were used to calculate body mass index (BMI)., Results: Thirty-nine percent of children were ages 3-8 years; 75% were black, 34% were obese (BMI ≥ 95 th percentile); vitamin D levels were >20 ng/ml in 55%. In linear regression analyses, post vaccination antibody titers for LAIV B lineages (B Brisbane and B Massachusetts) were significantly higher among those with lower vitamin D levels and among younger participants (P < 0.05). No associations between vitamin D levels and responses to LAIV A strains (A/H1N1 and A/H3N2) or to any IIV strains or lineages were found., Conclusion: Low vitamin D levels were associated with higher response to LAIV B lineages in the 2014-2015 LAIV, but not related to LAIV A or any IIV strains.

Background: The influenza B virus has two lineages; Yamagata and Victoria. The two lineages are antigenically distinct and it is difficult to expect cross-protection between the lineages. Actually, the mismatch between circulating influenza B viruses and vaccine strains has been occurred frequently. The cell-culture system for the production of influenza vaccine can contribute to improve vaccine strain selection and expand vaccine supplies. We investigated the immunogenicity and safety of cell culture-derived quadrivalent inactivated influenza vaccine (NBP607-QIV) in adults and elderly subjects., Methods: A randomized controlled phase III trial was undertaken in 10 university hospitals in the Republic of Korea (Clinical trial Number-NCT02467842). Adults (aged 19-59 years) and elderly subjects (aged ≥60 years) were randomly assigned in a 2:1:1 ratio to NBP607-QIV versus cell culture-based trivalent inactivated influenza vaccine-Yamagata (NBP607-Y) and cell culture-based trivalent inactivated influenza vaccine-Victoria (NBP607-V). Immunogenicity was assessed 3 weeks after vaccination by hemagglutination inhibition assay. Safety was assessed for 6 months post-vaccination: solicited adverse events (AEs) for 7 days, unsolicited AEs for 21 days and serious adverse events (SAEs) for 6 months. AEs were sub-classified as adverse drug reactions (ADRs) according to the causality., Results: A total of 1,503 participants were randomly assigned to NBP607-QIV (n = 752), NBP607-Y (n = 373) and NBP607-V (n = 378). The seroconversion rates of NBP607-QIV were 52.4%, 51.2%, 43.7% and 55.8% against A/H1N1, A/H3N2, B/Yamagata and B/Victoria, respectively. Non-inferiority against shared strains and superiority against alternate-lineage B strains were demonstrated for NBP607-QIV vs. NBP607-Y and NBP607-V. A total of 730 reactions occurred in 324 (43.1%) subjects of NBP607-QIV group. Majority of ADRs was solicited (99.2%) and mild (90.3%) in intensity. In adults (aged 19-59 years), solicited local AEs were slightly more frequent in NBP607-QIV group than NBP607-Y or NBP607-V group (40.9%, 33.4% and 32.5%, respectively). One SAE was observed among NBP607-QIV group, which was considered to be unrelated to the study vaccine within 3 weeks of vaccination and no vaccine-related SAEs were reported up to 6 months after vaccination., Conclusions: NBP607-QIV is a safe, well-tolerated and immunogenic influenza vaccine in Korean adults and elderly subjects.

In China, both inactivated hepatitis A (HA) vaccine and live attenuated HA vaccine are available. We conducted a trial to evaluate 5-year immune persistence induced by one dose of inactivated or live attenuated HA vaccines in children. Subjects with no HA vaccination history had randomly received one dose of inactivated or live attenuated HA vaccine at 18-60 months of age. Anti-HAV antibody concentrations were measured before vaccination and at the first, second, and fifth year after vaccination. Suspected cases of hepatitis A were monitored during the study period. A total of 332 subjects were enrolled and 182 provided evaluable serum samples at all planned time points. seropositive rate at 5 y was 85.9% in the inactivated HA vaccine group and 90.7% in the live attenuated HA vaccine group. GMCs were 76.3% mIU/ml (95% CI: 61.7 - 94.4) and 66.8mIU/ml (95% CI: 57.8 - 77.3), respectively. No significant difference in antibody persistence between 2 groups was found. No clinical hepatitis A case was reported. A single dose of an inactivated or live attenuated HA vaccine at 18-60 months of age resulted in high HAV seropositive rate and anti-HAV antibody concentrations that lasted for at least 5 y.

A split-virion trivalent inactivated influenza vaccine produced according to the Chinese pharmacopeia (Shz-IIV3) has been commercially available in China since 2014. Here, we describe the results of a phase IV open-label trial to describe the immunogenicity and safety of the 2014-2015 Northern Hemisphere formulation of Shz-IIV3 in individuals ≥ 6 months of age. Subjects 6-35 months of age received 2 half-doses of Shz-IIV3 (0.25 ml) 28 d apart, and subjects ≥ 3 y of age received a single full dose (0.5 ml). The study included 602 subjects. Except for the A (H3N2) strain in subjects 3-17 years, geometric mean hemagglutination inhibition titer ratios were ≥ 10 and rates of seroconversion/significant increase in titer were ≥ 78% in all age groups. For the H3N2 strain in subjects 3-17 years, the geometric mean titer ratio was 3.8 and the rate of seroconversion/significant increase was 56%. Post-vaccination seroprotection rates were ≥ 88% for all strains in all age groups. The most common solicited reactions were injection-site pain/tenderness and fever, most of which were grade 1 and resolved within 3 d. Vaccine-related unsolicited adverse events were reported only by subjects 6-23 months, most of which were mild abnormal crying and irritability. No vaccine-related serious adverse events and no deaths were reported. No new safety signals or unexpected safety events occurred, although an immediate anaphylactic skin reaction occurred in one subject. This study confirmed that the 2014-2015 Northern Hemisphere formulation of Shz-IIV3 was well tolerated and highly immunogenic in subjects ≥ 6 months of age.

Japanese encephalitis (JE) is a serious public health concern in most of Asia. The disease is caused by JE virus (JEV), a flavivirus transmitted by Culex mosquitoes. Several vaccines have been developed to control JE in endemic areas as well as to protect travelers and military personnel who visit or are commissioned from non-endemic to endemic areas. The vaccines include inactivated vaccines produced in mouse brain or cell cultures, live attenuated vaccines, and a chimeric vaccine based on the live attenuated yellow fever virus 17D vaccine strain. All the marketed vaccines belong to the JEV genotype III, but have been shown to be efficacious against other genotypes and strains, with varying degrees of cross-neutralization, albeit at levels deemed to be protective. The protective responses have been shown to last three or more years, depending on the type of vaccine and the number of doses. This review presents a brief account of the different JE vaccines, their immunogenicity and protective ability, and the impact of JE vaccines in reducing the burden of disease in endemic countries.

Influenza viral infections are significant global public health concerns due to the morbidity and mortality associated with acute respiratory disease, secondary complications, and pandemic threats; thus, continuous efforts have been made to develop potent influenza vaccines. In this study, 3 different mucosal adjuvants-alkyl polyglycoside (APG), gellan gum, and chitosan (CS)-were evaluated for their efficacy in intranasal A/H1N1 or B split influenza vaccines administered to BALB/c mice. Protective immunity was monitored by serum analysis for IgG, hemagglutination inhibition (HI), and neutralizing antibody levels, as well as mucosal IgA levels in nasal and pulmonary lavage fluids. Survival, body weight, lung viral titer, and pulmonary immunopathology were also examined following lethal influenza challenge. Notably, all adjuvants amplified the IgG and IgA immune responses (not detected in immunization of influenza B) and increased survival rate compared with controls administered adjuvant-free intranasal vaccines. Alternatively, intramuscular immunization stimulated IgG production, but had no effect on IgA levels. Our collective analysis identified that APG was the most effective intranasal adjuvant, as all mice survived influenza challenge with limited body weight loss, viral titer, and pulmonary pathology, similar to those observed with intramuscular vaccination. This evidence supports that APG can elicit both systemic and mucosal immunity, and may be an effective adjuvant in intranasal split influenza A/H1N1 and B vaccines.

In the 2015/16 influenza season, the Canadian National Advisory Committee on Immunization (NACI) recommended vaccination with quadrivalent inactivated influenza vaccine (QIV) for infants aged 6-23 months and trivalent inactivated influenza vaccines (TIVs) or QIVs in adults. The objective of this review (GSK study identifier: HO-13-14054) is to examine the epidemiology and disease burden of influenza in Canada and the economic benefits of vaccination. To inform this review, we performed a systematic literature search of relevant Canadian literature and National surveillance data. Influenza B viruses from phylogenetically-distinct lineages (B/Yamagata and B/Victoria) co-circulate in Canada, and are an important cause of influenza complications. Modeling studies, including those postdating the search suggest that switching from TIV to QIV in Canada reduces the burden of influenza and would likely be cost-effective. However, more robust real-world outcomes data is required to inform health policy decision makers on appropriate influenza vaccination strategies for Canada.

Pertussis is one of the most prevalent vaccine-preventable diseases worldwide. The true infection rate is significantly higher than the reported incidence rate. An increased prevalence of pertussis in older populations has been found, mainly caused by waning immunity after vaccination. Vaccine-induced immunity differs due to variation in vaccine content, schedule and coverage. Protection following acellular pertussis vaccines has been suggested to wane faster than whole cell pertussis vaccines. However, long-term immune persistence of whole cell pertussis vaccines may be confounded by a progressive acquisition of natural immunity. The World Health Organization has recommended that a switch from whole cell to acellular pertussis vaccines for primary immunization in infants should only be considered if additional periodic boosters or maternal immunization can be ensured and sustained in the national immunization schedules. In this review, we present data on immune persistence after different pertussis vaccinations and compare the findings from countries with different vaccination strategies. Future aspects in serological studies are briefly discussed.

The WHO recommends integration of universal mass vaccination (UMV) against hepatitis A virus (HAV) in national immunization schedules for children aged ≥1 year, if justified on the basis of acute HAV incidence, declining endemicity from high to intermediate and cost-effectiveness. This recommendation has been implemented in several countries. Our aim was to assess the impact of UMV using monovalent inactivated hepatitis A vaccines on incidence and persistence of anti-HAV (IgG) antibodies in pediatric populations. We conducted a systematic review of literature published between 2000 and 2015 in PubMed, Cochrane Library, LILACS, IBECS identifying a total of 27 studies (Argentina, Belgium, China, Greece, Israel, Panama, the United States and Uruguay). All except one study showed a marked decline in the incidence of hepatitis A post introduction of UMV. The incidence in non-vaccinated age groups decreased as well, suggesting herd immunity but also rising susceptibility. Long-term anti-HAV antibody persistence was documented up to 17 y after a 2-dose primary vaccination. In conclusion, introduction of UMV in countries with intermediate endemicity for HAV infection led to a considerable decrease in the incidence of hepatitis A in vaccinated and in non-vaccinated age groups alike.

Cholera remains an important but neglected public health threat, affecting the health of the poorest populations and imposing substantial costs on public health systems. Cholera can be eliminated where access to clean water, sanitation, and satisfactory hygiene practices are sustained, but major improvements in infrastructure continue to be a distant goal. New developments and trends of cholera disease burden, the creation of affordable oral cholera vaccines (OCVs) for use in developing countries, as well as recent evidence of vaccination impact has created an increased demand for cholera vaccines. The global OCV stockpile was established in 2013 and with support from Gavi, has assisted in achieving rapid access to vaccine in emergencies. Recent WHO prequalification of a second affordable OCV supports the stockpile goals of increased availability and distribution to affected populations. It serves as an essential step toward an integrated cholera control and prevention strategy in emergency and endemic settings.