Preclinical evaluation of a plant-derived SARS-CoV-2 subunit vaccine: Protective efficacy,immunogenicity, safety,and toxicity

Coronavirus disease 2019 (COVID-19) is an acute respiratory illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The prevention of SARS-CoV-2 transmission has become a global priority. Previously, we showed that a protein subunit vaccine that was developed based on the fusion of the SARS-CoV-2 receptor-binding domain (RBD) to the Fc portion of human IgG1 (RBD-Fc), produced in Nicotiana benthamiana, and adjuvanted with alum, namely, Baiya SARS-CoV-2 Vax 1, induced potent immunological responses in both mice and cynomolgus monkeys. Hence, this study evaluated the protective efficacy, safety, and toxicity of Baiya SARS-CoV-2 Vax 1 in K18-hACE2 mice, monkeys and Wistar rats. Two doses of vaccine were administered three weeks apart on Days 0 and 21. The administration of the vaccine to K18-hACE2 mice reduced viral loads in the lungs and brains of the vaccinated animals and protected the mice against challenge with SARS-CoV-2. In monkeys, the results of safety pharmacology tests, general clinical observations, and a core battery of studies of three vital systems, namely, the central nervous, cardiovascular, and respiratory systems, did not reveal any safety concerns. The toxicology study of the vaccine in rats showed no vaccine-related pathological changes, and all the animals remained healthy under the conditions of this study. Furthermore, the vaccine did not cause any abnormal toxicity in rats and was clinically tolerated even at the highest tested concentration. In addition, general health status, body temperature, local toxicity at the administration site, hematology, and blood chemistry parameters were also monitored. Overall, this work presents the results of the first systematic study of the safety profile of a plant-derived vaccine, Baiya SARS-CoV-2 Vax 1; this approach can be considered a viable strategy for the development of vaccines against COVID-19.     

Immunogenicity and safety of an E. coli-produced bivalent human papillomavirus (type 16 and 18) vaccine: A randomized controlled phase 2 clinical trial

BackgroundThis study aimed to investigate the dosage, immunogenicity and safety profile of a novel human papillomavirus (HPV) types 16 and 18 bivalent vaccine produced by E. coli.MethodsThis randomized, double-blinded, controlled phase 2 trial enrolled women aged 18–25 years in China. Totally 1600 eligible participants were randomized to receive 90 μg, 60 μg, or 30 μg of the recombinant HPV 16/18 bivalent vaccine or the control hepatitis B vaccine on a 0, 1 and 6 month schedule. The designated doses are the combined micrograms of HPV16 and 18 VLPs with dose ratio of 2:1. The immunogenicity of the vaccines was assessed by measuring anti-HPV 16 and 18 neutralizing antibodies and total IgG antibodies. Safety of the vaccine was assessed.ResultsAll but one of the seronegative participants who received 3 doses of the HPV vaccines seroconverted at month 7 for anti-HPV 16/18 neutralizing antibodies and IgG antibodies. For HPV 16, the geometric mean titers (GMTs) of the neutralizing antibodies were similar between the 60 μg (GMT = 10,548) and 90 μg (GMT = 12,505) HPV vaccine groups and were significantly higher than those in the 30 μg (GMT = 7596) group. For HPV 18, the GMTs of the neutralizing antibodies were similar among the 3 groups. The HPV vaccine was well tolerated. No vaccine-associated serious adverse events were identified.ConclusionThe prokaryotic-expressed HPV vaccine is safe and immunogenic in women aged 18–25 years. The 60 μg dosage formulation was selected for further investigation for efficacy.Clinical trials registration: NCT01356823.     

Receptor-binding domain recombinant protein on alum-CpG induces broad protection against SARS-CoV-2 variants of concern

We conducted preclinical studies in mice using a yeast-produced SARS-CoV-2 RBD subunit vaccine candidate formulated with aluminum hydroxide (alum) and CpG deoxynucleotides. This formulation is equivalent to the Corbevax^TM vaccine that recently received emergency use authorization by the Drugs Controller General of India. We compared the immune response of mice vaccinated with RBD/alum to mice vaccinated with RBD/alum + CpG. We also evaluated mice immunized with RBD/alum + CpG and boosted with RBD/alum. Mice were immunized twice intramuscularly at a 21-day interval. Compared to two doses of the /alum formulation, the RBD/alum + CpG vaccine induced a stronger and more balanced Th1/Th2 cellular immune response, with high levels of neutralizing antibodies against the original Wuhan isolate of SARS-CoV-2 as well as the B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 and (Delta) variants. Neutralizing antibody titers against the B.1.1.529 (BA.1, Omicron) variant exceeded those in human convalescent plasma after Wuhan infection but were lower than against the other variants. Interestingly, the second dose did not benefit from the addition of CpG, possibly allowing dose-sparing of the adjuvant in the future. The data reported here reinforces that the RBD/alum + CpG vaccine formulation is suitable for inducing broadly neutralizing antibodies against SARS-CoV-2, including variants of concern.     

The swine CD81 enhances E2-based DNA vaccination against classical swine fever

Classical swine fever (CSF) is a highly contagious and economically important viral disease that affects the pig industry worldwide. The glycoprotein E2 of CSFV can induce neutralizing antibodies and protective immunity, and is widely used for novel vaccine development. The objective of this study was to explore whether a tetraspanin molecule CD81 could improve the immune responses of an E2-based DNA vaccine. Plasmids pVAX-CD81, pVAX-E2 and pVAX-CD81-E2 were constructed and the expression of target proteins was confirmed in BHK-21 cells by indirect immunofluorescence assay. BALB/c mice were divided into 5 groups and immunized with different plasmids (pVAX-E2, pVAX-CD81-E2, pVAX-E2 + pVAX-CD81, pVAX-CD81 and PBS) three times with two weeks interval. The results showed that the introduction of CD81 promoted higher humoral and cellular immune responses than E2 expression alone (P < 0.05). In addition, immunization with pVAX-CD81-E2 induced stronger immune responses than pVAX-E2 + pVAX-CD81. Furthermore, four groups of pigs were immunized with pVAX-E2, pVAX-CD81-E2, pVAX-CD81 and PBS, respectively. Humoral and cellular immune responses detection showed similar results with those in mice. Compared to pVAX-E2, pVAX-CD81-E2 induced higher titers of neutralizing antibodies after viral challenge and conferred stronger protection. These results confirmed the capacity of swine CD81 enhancing the humoral and cellular responses with an adjuvant effect on CSFV DNA vaccine. This is the first report demonstrating the adjuvant effect of CD81 to enhance the DNA vaccination for swine pathogen.     

CHRONOVAC VOYAGEUR: A study of the immune response to yellow fever vaccine among infants previously immunized against measles

For administration of multiple live attenuated vaccines, the Advisory Committee on Immunization Practices recommends either simultaneous immunization or period of at least 28 days between vaccines, due to a possible reduction in the immune response to either vaccine.The main objective of this study was to compare the immune response to measles (alone or combined with mumps and rubella) and yellow fever vaccines among infants aged 6–24 months living in a yellow fever non-endemic country who had received measles and yellow fever vaccines before travelling to a yellow fever endemic area.Subjects and methods: A retrospective, multicenter case-control study was carried out in 7 travel clinics in the Paris area from February 1st 2011 to march 31, 2015. Cases were defined as infants immunized with the yellow fever vaccine and with the measles vaccine, either alone or in combination with mumps and rubella vaccine, with a period of 1–27 days between each immunization. For each case, two controls were matched based on sex and age: a first control group (control 1) was defined as infants having received the measles vaccine and the yellow fever vaccine simultaneously; a second control group (control 2) was defined as infants who had a period of more than 27 days between receiving the measles vaccine and yellow fever vaccine.The primary endpoint of the study was the percentage of infants with protective immunity against yellow fever, measured by the titer of neutralizing antibodies in a venous blood sample.Results: One hundred and thirty-one infants were included in the study (62 cases, 50 infants in control 1 and 19 infants in control 2). Of these, 127 (96%) were shown to have a protective titer of yellow fever antibodies. All 4 infants without a protective titer of yellow fever antibodies were part of control group 1.Discussion: The measles vaccine, alone or combined with mumps and rubella vaccines, appears to have no influence on humoral immune response to the yellow fever vaccine when administered between 1 and 27 days. The absence of protective antibodies against yellow fever was observed only among infants who received both vaccines simultaneously.Conclusion: These results may support a revision of current vaccination recommendations concerning the administration of these two live attenuated vaccines either on the same day or at least 28 days apart. Our findings show no statistically significant difference if the interval between both vaccines is more than 24 h, but the immune response seems to be reduced when the two vaccines are given at the same time.     

A novel subunit vaccine co-expressing GM-CSF and PCV2b Cap protein enhances protective immunity against porcine circovirus type 2 in piglets

Porcine circovirus type 2 (PCV2) causes porcine circovirus-associated disease. Capsid (Cap) protein of PCV2 is the principal immunogenic protein that induces neutralizing antibodies and protective immunity. GM-CSF is an immune adjuvant that enhances responses to vaccines. In this study, recombinant baculoviruses Ac-Cap and Ac-Cap-GM-CSF expressing the Cap protein alone and co-expressing the Cap protein and porcine GM-CSF, respectively, were constructed successfully. The target proteins were analyzed by western blotting and IFA. Further, these proteins were confirmed by electron microscopy, which showed that Cap proteins could self-assemble into virus-like particles having diameters of 17–25 nm. Animal experiments showed that pigs immunized with Cap-GM-CSF subunit vaccine showed significantly higher levels of PCV2-specific antibodies and neutralizing antibodies than pigs immunized with the Cap subunit vaccine and a commercial vaccine (Ingelvac CircoFLEX; P < 0.05). After PCV2 wild strain challenged, Pigs receiving the Cap-GM-CSF subunit vaccine showed significantly higher average daily weight gain after wild-type PCV2 challenge than pigs receiving the other three vaccines (P < 0.05). None of PCV2 DNA was detected in all immunized animals, except control animals immunized with phosphate-buffered saline. These results indicated that GM-CSF was a powerful immunoadjuvant for PCV2 subunit vaccines because it enhanced humoral immune response and improved immune protection against PCV2 infection in pigs. Thus, the novel Cap-GM-CSF subunit vaccine has the potential to be used as an effective and safe vaccine candidate against PCV2 infection.     

Safety and efficacy of COVID-19 prime-boost vaccinations: Homologous BBIBP-CorV versus heterologous BNT162b2 boosters in BBIBP-CorV-primed individuals

BackgroundBooster vaccine doses against SARS-CoV-2 have been advocated to address evidence of waning immunity, breakthrough infection, and the emergence of immune-evasive variants. A heterologous prime-boost vaccine strategy may offer advantages over a homologous approach, but the safety and efficacy of this approach with the mRNA vaccine BNT162b2 (BNT: Pfizer) and inactivated BBIBP-CorV (BBIBT: Sinopharm) vaccines have not been studied.MethodsWe conducted a non-randomized, non-blinded phase II observational community trial across Bahrain, investigating the reactogenic and immunogenic response of participants who had previously received two doses of BBIBP, followed by a third booster dose of either BBIBP (homologous booster) or BNT (heterologous booster). Immunogenicity through serological status was determined at baseline and on the following 8th week. Reactogenicity data (safety and adverse events) were collected throughout study period, in addition to participant-led electronic journaling.Results305 participants (152 BBIBP and 153 BNT booster) were enrolled in the study, with 246 (127 BBIBP and 119 BNT booster) included in the final analysis. There was a significant increase in anti-SARS-CoV-2 antibody levels post booster administration in both groups; however, the heterologous BNT arm demonstrated a significantly larger mean increase in the level of spike (S) antigen-specific antibodies (32.7-fold increase versus 2.6, p < 0.0001) and sVNT neutralising antibodies (3.4-fold increase versus 1.8, p < 0.0001), whereas the homologous arm demonstrated a significant increase in the levels of nucleocapsid (N) antigen-specific antibodies (3.8-fold increase versus none). Non-serious adverse events (injection site pain, fever, and fatigue) were more commonly reported in the heterologous arm, but no serious adverse events occurred.ConclusionHeterologous prime-boost vaccination with the mRNA BNT162b2 (Pfizer) vaccine in those who had received two doses of inactivated virus BBIBP-CorV (Sinopharm) vaccine demonstrated a more robust immune response against SARS-CoV-2 than the homologous BBIBP booster and appears safe and well tolerated.Clinical Trial Registry Number (ClinicalTrials.gov): NCT04993560.     

Comparison of monovalent glycoprotein B with bivalent gB/pp65 (GP83) vaccine for congenital cytomegalovirus infection in a guinea pig model: Inclusion of GP83 reduces gB antibody response but both vaccine approaches provide equivalent protection against pup mortality

Cytomegalovirus (CMV) subunit vaccine candidates include glycoprotein B (gB), and phosphoprotein ppUL83 (pp65). Using a guinea pig cytomegalovirus (GPCMV) model, this study compared immunogenicity, pregnancy outcome, and congenital viral infection following pre-pregnancy immunization with a three-dose series of modified vaccinia virus Ankara (MVA)-vectored vaccines consisting either of gB administered alone, or simultaneously with a pp65 homolog (GP83)-expressing vaccine. Vaccinated and control dams were challenged at midgestation with salivary gland-adapted GPCMV. Comparisons included ELISA and neutralizing antibody responses, maternal viral load, pup mortality, and congenital infection rates. Strikingly, ELISA and neutralization titers were significantly lower in the gB/GP83 combined vaccine group than in the gB group. However, both vaccines protected against pup mortality (63.2% in controls vs. 11.4% and 13.9% in gB and gB/GP83 combination groups, respectively; p < 0.0001). Reductions in pup viral load were noted for both vaccine groups compared to control, but preconception vaccination resulted in a significant reduction in GPCMV transmission only in the monovalent gB group (26/44, 59% v. 27/34, 79% in controls; p < 0.05). We conclude that, using the MVA platform, the addition of GP83 to a gB subunit vaccine interferes with antibody responses and diminishes protection against congenital GPCMV infection, but does not decrease protection against pup mortality.     

Immunogenicity and reactogenicity of BNT162b2 booster in BBIBP-CorV-vaccinated individuals compared with homologous BNT162b2 vaccination: Results of a pilot prospective cohort study from Lebanon

Facing new COVID-19 waves, the effectiveness of BBIBP-CorV has been noted to be low in countries whose populations were already administered two doses of the vaccine. Heterologous vaccination using ChAdOx1-S/BNT162b2 elicited higher immunogenicity compared with homologous immunization. BBIBP-CorV/BNT162b2 combination is worth testing. In this pilot prospective cohort study conducted at Makassed General Hospital, Beirut, Lebanon, from February 17, 2021, to June 30, 2021, we tested the safety and immunogenicity of a BNT162b2 booster dose in COVID-19-naïve individuals who had received two doses of the BBIBP-CorV vaccine. Heterologous booster vaccination was found to be safe and well tolerated. It was significantly associated with higher anti-spike IgG geometric mean titers compared to that after homologous BNT162b2 immunization in COVID-19-naïve individuals [(8040 BAU/mL, 95% confidence interval (CI), 4612–14 016) vs (1384 BAU/mL, 95% CI, 1063–1801), respectively, (P < 0.0001)]. In countries with limited access to mRNA vaccines and where populations have already received BBIBP-CorV, mixing BBIBP-CorV/BNT162b2 is seen to overcome the low immunogenicity induced by BBIBP-CorV alone, thus potentially providing protection against emerging variants.     

Evaluation of immune responses of stabilised SAT2 antigens of foot-and-mouth disease in cattle

Foot-and-mouth disease (FMD) vaccines with improved stability and less reliant on a cold-chain are needed to improve the longevity of immune responses elicited in animals. This is especially so for serotypes O and SAT2 which are unstable in mildly acidic pH conditions or at elevated temperatures leading to dissociation of the capsid (146S particle) and loss of immunogenicity. Previously, stabilised SAT2 viruses were generated by reverse genetic approaches and assessed in vitro and in vivo with a guinea pig trial. Here we investigated the efficacy and comparative immunological responses of two thermostable and wild-type SAT2 vaccines over 5 months followed by challenge. We assessed humoral immune responses elicited in cattle in terms of total and neutralizing antibodies and IgG1/2 isotyping; and cell-mediated responses of IFN-γ as in vitro markers of protection. Whilst there were significant differences in total and neutralizing antibodies for the vSAT2-93H group compared to other vaccinated groups after the first vaccination, there were no significant differences after the second immunization. Following intra-dermolingual challenge all vaccinated groups were fully protected as determined by the absence of generalized lesions. These results provide proof that two vaccine doses, consisting of SAT2 antigen combined with ISA206B adjuvant, administered 4–6 weeks apart were able to protect animals up to 5 months pv. Additionally, vSAT2-93Y had significantly higher levels of IFN-γ after challenge and had a lower clinical score indicative of better protection compared to other vaccinated groups and the importance of cell mediated responses and antigen stability in protection.     

The recombinant N-terminal domain of spike proteins is a potential vaccine against Middle East respiratory syndrome coronavirus (MERS-CoV) infection

The persistent public health threat of infection with the Middle East respiratory syndrome coronavirus (MERS-CoV) highlights the need for an effective MERS-CoV vaccine. Previous studies have focused mainly on the receptor-binding domain (RBD) on the spike protein of MERS-CoV. Herein, we investigated the immunogenicity and protective potential of the recombinant N-terminal domain (rNTD) of spike proteins as a vaccine candidate. BALB/c mice vaccinated with 5 or 10 μg of rNTD protein demonstrated a significant humoral immune response (serum IgG and neutralizing activity). Additionally, according to the enzyme-linked immunospot, intracellular cytokine staining, and cytometric bead array assays, significant and functional T-cell immunity was induced by 10 μg of the rNTD vaccination with aluminum and CpG adjuvant. Furthermore, rNTD-immunized mice showed reduced lung abnormalities in a MERS-CoV-challenge mouse model transfected with an adenoviral vector expressing human DPP4, showing protection consistent with that found with rRBD vaccination. These data show that rNTD induced potent cellular immunity and antigen-specific neutralizing antibodies in mice and that it demonstrated protective capacity against a viral challenge, indicating that rNTD is a vaccine candidate against MERS-CoV infection.     

Preclinical refinements of a broadly protective VLP-based HPV vaccine targeting the minor capsid protein,L2

An ideal prophylactic human papillomavirus (HPV) vaccine would provide broadly protective and long-lasting immune responses against all high-risk HPV types, would be effective after a single dose, and would be formulated in such a manner to allow for long-term storage without the necessity for refrigeration. We have developed candidate HPV vaccines consisting of bacteriophage virus-like particles (VLPs) that display a broadly neutralizing epitope derived from the HPV16 minor capsid protein, L2. Immunization with 16L2 VLPs elicited high titer and broadly cross-reactive and cross-neutralizing antibodies against diverse HPV types. In this study we introduce two refinements for our candidate vaccines, with an eye towards enhancing efficacy and clinical applicability in the developing world. First, we assessed the role of antigen dose and boosting on immunogenicity. Mice immunized with 16L2-MS2 VLPs at doses ranging from 2 to 25 μg with or without alum were highly immunogenic at all doses; alum appeared to have an adjuvant effect at the lowest dose. Although boosting enhanced antibody titers, even a single immunization could elicit strong and long-lasting antibody responses. We also developed a method to enhance vaccine stability. Using a spray dry apparatus and a combination of sugars & an amino acid as protein stabilizers, we generated dry powder vaccine formulations of our L2 VLPs. Spray drying of our L2 VLPs did not affect the integrity or immunogenicity of VLPs upon reconstitution. Spray dried VLPs were stable at room temperature and at 37 °C for over one month and the VLPs were highly immunogenic. Taken together, these enhancements are designed to facilitate implementation of a next-generation VLP-based HPV vaccine which addresses U.S. and global disparities in vaccine affordability and access in rural/remote populations.     

Modeling maternal fetal RSV F vaccine induced antibody transfer in guinea pigs

BackgroundProtection of newborns and young infants against RSV disease via maternal immunization mediated by transplacental transfer of antibodies is under evaluation in third-trimester pregnant women with the RSV recombinant F nanoparticle vaccine (RSV F vaccine). Since the hemichorial placental architecture in guinea pigs and humans is similar, the guinea pig model was employed to assess RSV F vaccine immunogenicity in pregnant sows and to compare RSV-specific maternal antibody levels in their pups.MethodsThirty (30) presumptive pregnant guinea pigs were immunized on gestational day 25 and 46 with placebo (PBS), 30 μg RSV F, or 30 μg RSV F + 400 μg aluminum phosphate. Sera at delivery/birth (sows/pups) and 15 and 30 days post-partum (pups) were analyzed for the presence of anti-F IgG, palivizumab-competitive antibody (PCA) and RSV/A microneutralization (MN).ResultsThe rates of pregnancy and stillbirth were similar between controls and vaccinees. The vaccine induced high levels of anti-F IgG, PCA and MN in sows, with the highest levels observed in adjuvanted vaccinees. Placental transfer to pups was proportional to the maternal antibody levels, with concentration effects observed for all immune measures.ConclusionsThe RSV F vaccine was safe and immunogenic in pregnant guinea pigs and supported robust transplacental antibody transfer to their pups. Relative concentration of antibodies in the pups was observed even in the presence of high levels of maternal antibody. Guinea pigs may be an important safety and immunogenicity model for preclinical assessment of candidate vaccines for maternal immunization.     

Preclinical and clinical development of a dengue recombinant subunit vaccine

This review focuses on a dengue virus (DENV) vaccine candidate based on a recombinant subunit approach which targets the DENV envelope glycoprotein (E). Truncated versions of E consisting of the N-terminal portion of E (DEN-80E) have been expressed recombinantly in the Drosophila S2 expression system and shown to have native-like conformation. Preclinical studies demonstrate that formulations containing tetravalent DEN-80E adjuvanted with ISCOMATRIX™ adjuvant induce high titer virus neutralizing antibodies and IFN-γ producing T cells in flavivirus-naïve non-human primates. The preclinical data further suggest that administration of such formulations on a 0, 1, 6 month schedule may result in higher maximum virus neutralizing antibody titers and better durability of those titers compared to administration on a 0, 1, 2 month schedule. In addition, the virus neutralizing antibody titers induced by adjuvanted tetravalent DEN-80E compare favorably to the titers induced by a tetravalent live virus comparator. Furthermore, DEN-80E was demonstrated to be able to boost virus neutralizing antibody titers in macaques that have had a prior DENV exposure. A monovalent version of the vaccine candidate, DEN1-80E, was formulated with Alhydrogel™ and studied in a proof-of-principle Phase I clinical trial by Hawaii Biotech, Inc. (NCT00936429). The clinical trial results demonstrate that both the 10 μg and 50 μg formulations of DEN1-80E with 1.25 mg of elemental aluminum were immunogenic when administered in a 3-injection series (0, 1, 2 months) to healthy, flavivirus-naïve adults. The vaccine formulations induced DENV-1 neutralizing antibodies in the majority of subjects, although the titers in most subjects were modest and waned over time. Both the 10 μg DEN1-80E and the 50 μg DEN1-80E formulations with Alhydrogel™ were generally well tolerated.     

No evidence of an increase of bacterial and viral infections following Measles,Mumps and Rubella vaccine

The suggestion that multi-antigen vaccines might overload the immune system has led to calls for single antigen vaccines. In 2003 we showed that rather than an increase there appeared to be a reduced risk of severe bacterial infection in the three months following Measles, Mumps and Rubella vaccine (MMR). The present analysis of illnesses in a general population is based on an additional 10 years of data for bacterial infections and also includes admissions with viral infections. Analyses were carried out using the self-controlled case-series method and separately for bacterial and viral infection cases, using risk periods of 0–30 days, 31–60 days and 61–90 days post MMR vaccine. An analysis was also carried out for those cases which were given MMR and Meningococcal serogroup C (MCC) vaccines concomitantly.A reduced risk was seen in the 0–30-day period for both bacterial infection (relative incidence = 0.68, 95% CI 0.54–0.86) and viral infections (relative incidence = 0.68, 95% CI 0.49–0.93). There was no increased risk in any period when looking at combined viral or bacterial infections or for individual infections with the single exception of an increased risk in the 31–60 days post vaccination period for herpes infections (relative incidence = 1.69, 95% CI 1.06–2.70). For the children given Meningococcal group C vaccines concomitantly no significantly increased risk was seen in either the bacterial (relative incidence = 0.54, 95% CI 0.26–1.13) or viral cases (relative incidence = 0.46, 95% CI 0.11–1.93).Our study confirms that the MMR vaccine does not increase the risk of invasive bacterial or viral infection in the 90 days after the vaccination and does not support the hypothesis that there is an induced immune deficiency due to overload from multi-antigen vaccines.     

A Phase 2 randomized,observer-blind,placebo-controlled,dose-ranging trial of aluminum-adjuvanted respiratory syncytial virus F particle vaccine formulations in healthy women of childbearing age

ObjectiveRespiratory syncytial virus (RSV) causes significant morbidity and mortality in infants. We are developing an RSV fusion (F) protein nanoparticle vaccine for immunization of third trimester pregnant women to passively protect infants through transfer of RSV-specific maternal antibodies. The present trial was performed to assess the immunogenicity and safety of several formulations of RSV F vaccine in 1-dose or 2-dose schedules.MethodsPlacebo, or vaccine with 60 μg or 120 μg RSV F protein and 0.2, 0.4, or 0.8 mg aluminum, were administered intramuscularly on Days 0 and 28 to healthy women 18–35 years old. Immunogenicity was assessed from Days 0 through 91 based on anti-F IgG and palivizumab-competitive antibody (PCA) by ELISA, and RSV A and B neutralizing antibodies by microneutralization (MN) assay. Solicited adverse events were collected through Day 7 and unsolicited adverse events through Day 91.ResultsAll formulations were well-tolerated, with no treatment-related serious adverse events. Anti-F IgG and PCA responses were correlated and increased after both doses, while MN increased significantly only after the first dose, then plateaued. The timeliest and most robust antibody responses followed one dose of 120 μg RSV F protein and 0.4 mg aluminum, but persistence through 91 days was modestly (∼25%) superior following two doses of 60 μg RSV F protein and 0.8 mg aluminum. Western blot analysis showed RSV infections in active vaccinees were reduced by 52% overall (p = 0.009 overall) over the Day 0 through 90 period.ConclusionsRSV F nanoparticle vaccine formulations were well tolerated and immunogenic. The optimal combination of convenience and rapid response for immunization in the third trimester occurred with 120 μg RSV F and 0.4 mg aluminum, which achieved peak immune responses in 14 days and sufficient persistence through 91 days to allow for passive transfer of IgG antibodies to the fetus. NCT01960686.     

The role of parental attitudes and provider discussions in uptake of adolescent vaccines

The purpose of this study was to examine the relationship between parental vaccine attitudes, the number of specific vaccines discussed with a provider, and immunization outcomes including discussing immunization with their teen, knowledge of adolescent vaccine schedule, and their son or daughter being up-to-date on recommended vaccines using a nationally weight sample. Parents completed an internet-based survey between December 2012 and January 2013 and we computed a vaccine attitude scale (higher scores indicating stronger and more positive attitudes toward vaccination of teen) for each parent and categorized them into one of three groups: low (n = 76), medium (n = 207) or high (n = 215). We also constructed a vaccine discussion scale representing the number of vaccines discussed with their adolescent's physician. Parents who were identified as having high vaccine attitudes were significantly more likely to report their physician talked with them about a particular vaccine. Using logistic regression and controlling for respondent's gender and age, income, and teen's gender, we found medium as compared to low-attitude parents had a 6.21 (95%CI = 3.08, 12.51) greater odds of reporting that their teen had all recommended vaccines. Similarly, high as compared to low-attitude parents reported a 23.02 (95% CI = 11.27, 46.99) greater odds of having a teen who was up-to-date on recommended vaccines. We detected that for each additional vaccine discussed, there was a 1.24 (95%CI = 1.11, 1.39) increase in odds of the teen having all recommended vaccines. Parental immunization attitudes and provider discussion about vaccines are key ingredients to improving immunization rates among adolescents. While some parents may be reluctant to immunize their son or daughter with a recommended vaccine, vaccine-specific discussions between physicians and parents represent an important first step to continued discussions with providers regarding vaccination. Moreover, vaccine discussions must occur within the context of ongoing conversations about health and disease prevention.     

What vaccine product attributes do immunization program stakeholders value? Results from interviews in six low- and middle-income countries

This study attempts to capture the opinions of stakeholders working in immunization programs in low- and middle-income countries to understand how vaccine products could be improved to better meet their needs and to obtain feedback on specific vaccine product attributes including the number of doses per container and ease of preparing a dose for administration. We also reviewed how procurement decisions are made within immunization programs. Semi-structured interviews were undertaken with 158 immunization stakeholders in Brazil, China, India, Peru, the Philippines, and Tanzania. Interviewees included national decision-makers and advisors involved in vaccine-purchasing decisions (n = 30), national Expanded Programme on Immunization managers (n = 6), and health and logistics personnel at national, subnational, and health-facility levels (n = 122).Immunization stakeholders at all levels of the supply chain valued vaccine product attributes that prevent heat damage, decrease vaccine wastage, and simplify delivery. Minimizing the time required to prepare a dose is especially valued by those closest to the work of actually administering vaccines. Respondents appreciated the benefits of lower-multidose presentations on reducing wastage but seemed to prefer single-dose vials even more. They also expressed concern about the need for training and the potential for confusion and vial contamination if opened vials of liquid preservative-free vaccines are not handled properly. Procurement decision-making processes varied widely between countries, though most relied heavily on international agencies and vaccine manufacturers for information.     

Recombinant measles virus encoding the spike protein of SARS-CoV-2 efficiently induces Th1 responses and neutralizing antibodies that block SARS-CoV-2 variants

Owing to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants, the development of effective and safe vaccines has become a priority. The measles virus (MeV) vaccine is an attractive vaccine platform as it has been administered to children for more than 40 years in over 100 countries. In this study, we developed a recombinant MeV expressing the full-length SARS-CoV-2 spike protein (rMeV-S) and tested its efficacy using mouse and hamster models. In hCD46Tg mice, two-dose rMeV-S vaccination induced higher Th1 secretion and humoral responses than one-dose vaccination. Interestingly, neutralizing antibodies induced by one-dose and two-dose rMeV-S immunization effectively blocked the entry of the α, β, γ, and δ variants of SARS-CoV-2. Furthermore, two-dose rMeV-S immunization provided complete protection against SARS-CoV-2 in the hamster model. These results suggest the potential of rMeV-S as a vaccine candidate for targeting SARS-CoV-2 and its variants.     

Effect of introduction of pentavalent vaccine as replacement for Diphtheria–Tetanus–Pertussis and Hepatitis B vaccines on vaccination uptake in a health facility in Nigeria

BackgroundThe introduction of a new vaccine into an immunization programme may affect the immunization system negatively or positively. The aim of this study is to determine the effect of the introduction of the pentavalent vaccine as replacement for DTP and Hepatitis B vaccines on timeliness, completion of the schedule and dropout rates among children attending a health facility.MethodologyThis was a retrospective cohort study which involved extracting immunization records of children attending the Institute of Child Health Child Welfare Clinic between June 2011 and May 2013. Pentavalent vaccine was introduced as a replacement for DTP and Hepatitis B vaccines in June 2012. The uptake, timeliness and dropout rates of different vaccines in the immunization schedule were determined for children who commenced immunization in the pre, peri and post introduction phases.ResultsA total of 1110 children were studied – 190, 410 and 510 who commenced vaccination in the pre, peri and post introduction phases of the pentavalent vaccine respectively. Uptake was significantly higher for all vaccines in the post introduction phase compared to pre and peri introduction phases (p < 0.001). Completion of the immunization schedule by 60.2% of the children who commenced vaccination in the post introduction phase was higher than the 31.6% and 41.7% for the pre and peri introduction phases respectively (p < 0.001). Significantly more visits were required to complete the schedule in the peri introduction phase compared to the pre and post introduction phases p < 0.001. Delay in receipt of the three doses of DTP/PENTA was significantly longer in the peri introduction phase compared to pre and post introduction phases.ConclusionThe introduction of pentavalent vaccine significantly improved uptake of vaccines and completion of the schedule but resulted in prolonged delay in receipt of vaccines during the introduction period.