Preimmunization correlates of protection shared across malaria vaccine trials in adults

Identifying preimmunization biological characteristics that promote an effective vaccine response offers opportunities for illuminating the critical immunological mechanisms that confer vaccine-induced protection, for developing adjuvant strategies, and for tailoring vaccination regimens to individuals or groups. In the context of malaria vaccine research, studying preimmunization correlates of protection can help address the need for a widely effective malaria vaccine, which remains elusive. In this study, common preimmunization correlates of protection were identified using transcriptomic data from four independent, heterogeneous malaria vaccine trials in adults. Systems-based analyses showed that a moderately elevated inflammatory state prior to immunization was associated with protection against malaria challenge. Functional profiling of protection-associated genes revealed the importance of several inflammatory pathways, including TLR signaling. These findings, which echo previous studies that associated enhanced preimmunization inflammation with protection, illuminate common baseline characteristics that set the stage for an effective vaccine response across diverse malaria vaccine strategies in adults.

Zika virus baculovirus-expressed envelope protein elicited humoral and cellular immunity in immunocompetent mice

Zika virus (ZIKV) is a mosquito-borne virus that has a high risk of inducing Guillain–Barré syndrome and microcephaly in newborns. Because vaccination is considered the most effective strategy against ZIKV infection, we designed a recombinant vaccine utilizing the baculovirus expression system with two strains of ZIKV envelope protein (MR766, Env_M; ZBRX6, Env_Z). Animals inoculated with Env_M and Env_Z produced ZIKV-specific antibodies and secreted effector cytokines such as interferon-γ, tumor necrosis factor-α, and interleukin-12. Moreover, the progeny of immunized females had detectable maternal antibodies that protected them against two ZIKV strains (MR766 and PRVABC59) and a Dengue virus strain. We propose that the baculovirus expression system ZIKV envelope protein recombinant provides a safe and effective vaccine strategy.

Benign Fasciculation Syndrome and Migraine Aura without Headache: Possible Rare Side Effects of the BNT162b2 mRNA Vaccine? A Case Report and a Potential Hypothesis

The BNT162b2 (Pfizer BioNTech) mRNA vaccine is an effective vaccine against COVID-19 infection. Here, we report an adverse event following immunization (AEFI) in a 48-year-old female patient who presented with fasciculations, migraine auras without headaches and in an increased discomfort of previously present palpitations, as well as excitation and insomnia. Her fasciculations were intermittently present until the time this paper was written, starting from the 6th day post-vaccination; they changed localization and frequency, but most commonly they were generalized, affecting almost all muscle groups. The patient also suffered from two incidents of migraine auras with visual kaleidoscope-like phenomena without headaches a few months after the vaccination. These symptoms were considered to be AEFI and no causal relation with the vaccine could be proven.

Venezuelan Equine Encephalitis Virus V3526 Vaccine RNA-Dependent RNA Polymerase Mutants Increase Vaccine Safety Through Restricted Tissue Tropism in a Mouse Model

Background: Venezuelan equine encephalitis virus (VEEV) is an arbovirus endemic to the Americas, for which no vaccines or antiviral agents have been approved. TC-83 and V3526 are the best-characterized vaccine candidates for VEEV. Both are live-attenuated vaccines and have been associated with safety concerns, although fewer concerns exist for V3526. A previous attempt to improve the TC-83 vaccine focused on further attenuating the vaccine by adding mutations that alter the error-incorporation rate of the RNA-dependent RNA polymerase (RdRp). Methods: The research herein examined the effects of these RdRp mutations in V3526 by cloning the 3X and 4X strains, assessing vaccine efficacy against challenge in adult female CD-1 mice, examining neutralizing-antibody titers, investigating vaccine tissue tropism, and testing the stability of the mutant strains. Results: The V3526 RdRp mutants exhibited less tissue tropism in the spleen and kidney than the wild-type V3526, while maintaining vaccine efficacy. Illumina sequencing indicated that the RdRp mutations reverted to wild-type V3526 after five passages in murine pup brains. Conclusions: The observed genotypic reversion is likely to be of limited concern, because wild-type V3526 remains an effective vaccine capable of providing protection. Our results indicate that the V3526 RdRp mutants may be a safer vaccine design than the original V3526.

Immunogenicity and Protective Capacity of a Virus-like Particle Vaccine against Chlamydia trachomatis Type 3 Secretion System Tip Protein, CT584

An effective vaccine against Chlamydia trachomatis is urgently needed as infection rates continue to rise and C. trachomatis causes reproductive morbidity. An obligate intracellular pathogen, C. trachomatis employs a type 3 secretion system (T3SS) for host cell entry. The tip of the injectosome is composed of the protein CT584, which represents a potential target for neutralization with vaccine-induced antibody. Here, we investigate the immunogenicity and efficacy of a vaccine made of CT584 epitopes coupled to a bacteriophage virus-like particle (VLP), a novel platform for Chlamydia vaccines modeled on the success of HPV vaccines. Female mice were immunized intramuscularly, challenged transcervically with C. trachomatis, and assessed for systemic and local antibody responses and bacterial burden in the upper genital tract. Immunization resulted in a 3-log increase in epitope-specific IgG in serum and uterine homogenates and in the detection of epitope-specific IgG in uterine lavage at low levels. By contrast, sera from women infected with C. trachomatis and virgin controls had similarly low titers to CT584 epitopes, suggesting these epitopes are not systemically immunogenic during natural infection but can be rendered immunogenic by the VLP platform. C. trachomatis burden in the upper genital tract of mice varied after active immunization, yet passive protection was achieved when immune sera were pre-incubated with C. trachomatis prior to inoculation into the genital tract. These data demonstrate the potential for antibody against the T3SS to contribute to protection against C. trachomatis and the value of VLPs as a novel platform for C. trachomatis vaccines.

Optimization of SARS-CoV-2 Spike Protein Expression in the Silkworm and Induction of Efficient Protective Immunity by Inoculation With Alum Adjuvants

The newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing a spread of coronavirus disease 2019 (COVID-19) globally. In order to end the COVID-19 pandemic, an effective vaccine against SARS-CoV-2 must be produced at low cost and disseminated worldwide. The spike (S) protein of coronaviruses plays a pivotal role in the infection to host cells. Therefore, targeting the S protein is one of the most rational approaches in developing vaccines and therapeutic agents. In this study, we optimized the expression of secreted trimerized S protein of SARS-CoV-2 using a silkworm-baculovirus expression vector system and evaluated its immunogenicity in mice. The results showed that the S protein forming the trimeric structure was the most stable when the chicken cartilage matrix protein was used as the trimeric motif and could be purified in large amounts from the serum of silkworm larvae. The purified S protein efficiently induced antigen-specific antibodies in mouse serum without adjuvant, but its ability to induce neutralizing antibodies was low. After examining several adjuvants, the use of Alum adjuvant was the most effective in inducing strong neutralizing antibody induction. We also examined the adjuvant effect of paramylon from Euglena gracilis when administered with the S protein. Our results highlight the effectiveness and suitable construct design of the S protein produced in silkworms for the subunit vaccine development against SARS-CoV-2.

Analysis of non-pharmaceutical interventions and their impacts on COVID-19 in Kerala

In the absence of an effective vaccine or drug therapy, non-pharmaceutical interventions are the only option for control of the outbreak of the coronavirus disease 2019, a pandemic with global implications. Each of the over 200 countries affected has followed its own path in dealing with the crisis, making it difficult to evaluate the effectiveness of measures implemented, either individually, or collectively. In this paper we analyse the case of the south Indian state of Kerala, which received much attention in the international media for its actions in containing the spread of the disease in the early months of the pandemic, but later succumbed to a second wave. We use a model to study the trajectory of the disease in the state during the first four months of the outbreak. We then use the model for a retrospective analysis of measures taken to combat the spread of the disease, to evaluate their impact. Because of the differences in the trajectory of the outbreak in Kerala, we argue that it is a model worthy of a place in the discussion on how the world might best handle this and other, future, pandemics.

HiSpike Method for High-Throughput Cost Effective Sequencing of the SARS-CoV-2 Spike Gene

The changing nature of the SARS-CoV-2 pandemic poses unprecedented challenges to the world's health systems. Emerging spike gene variants jeopardize global efforts to produce immunity and reduce morbidity and mortality. These challenges require effective real-time genomic surveillance solutions that the medical community can quickly adopt. The SARS-CoV-2 spike protein mediates host receptor recognition and entry into the cell and is susceptible to generation of variants with increased transmissibility and pathogenicity. The spike protein is the primary target of neutralizing antibodies in COVID-19 patients and the most common antigen for induction of effective vaccine immunity. Tight monitoring of spike protein gene variants is key to mitigating COVID-19 spread and generation of vaccine escape mutants. Currently, SARS-CoV-2 sequencing methods are labor intensive and expensive. When sequence demands are high sequencing resources are quickly exhausted. Consequently, most SARS-CoV-2 strains are sequenced in only a few developed countries and rarely in developing regions. This poses the risk that undetected, dangerous variants will emerge. In this work, we present HiSpike, a method for high-throughput cost effective targeted next generation sequencing of the spike gene. This simple three-step method can be completed in < 30 h, can sequence 10-fold more samples compared to conventional methods and at a fraction of their cost. HiSpike has been validated in Israel, and has identified multiple spike variants from real-time field samples including Alpha, Beta, Delta and the emerging Omicron variants. HiSpike provides affordable sequencing options to help laboratories conserve resources for widespread high-throughput, near real-time monitoring of spike gene variants.

Nanodiamonds in Oil Emulsions as Effective Vaccine Adjuvants and Antitumor Therapeutic Agents

Background Composed of mineral oil and mycobacteria pathogens, complete Freund’s adjuvant (CFA) is one of the most commonly used adjuvants for antibody production and scientific research due to its high efficiency. However, the dead mycobacteria in CFA can cause many allergic reactions. We propose here a new formulation based on the use of nanodiamonds (NDs) as biocompatible non-allergic additives in incomplete Freund’s adjuvant (IFA) to avoid these adverse effects. Methods Chicken egg ovalbumin (OVA) was used as the antigens and 100-nm NDs after purification by air oxidation and strong oxidative acid washes were used as the additives. Levels of OVA-specific IgG antibody in mouse sera were measured by using enzyme-linked immunosorbent assays (ELISA) after the second and third immunizations of healthy mice with OVA and OVA/ND in IFA or CFA. Abilities of the OVA/ND/IFA vaccination to inhibit the tumor growth of mice inoculated with EL4 cells or OVA-expressing E.G7 cells were examined over 1 month. Results The new formulation worked well as a potent vaccine adjuvant, which could boost the immune responses and reduce the consumption of antigens in producing antibodies of interest in model animals like mice. Additionally, the composites showed distinct therapeutic activities, as proven by the OVA/ND/IFA treatment that effectively inhibited the tumor progression of E.G7-inoculated mice, allowing the animals to survive over 35 days post tumor-cell challenges. About 0.2% of the injected ND particles were found in mouse spleens on day 24 after vaccination of the E.G7-inoculated mice with OVA/ND/IFA. Conclusions The multiple functionality of ND makes it useful as an active and trackable component of a vaccine adjuvant not only to enhance antibody production but also to suppress tumor growth in vivo. The ND-based new formulation can be developed into single-dose vaccines with promising potential for real-world applications.

Resistance to Persuasion: Examining the Influence of Political Ideology on COVID-19 Vaccine Uptake Hesitancy

The COVID-19 pandemic has contributed to the death of over 625,000 Americans and it continues to have monumental consequences worldwide for economic, social and individual life. An effective vaccine program is considered vital to securing collective immunity; yet, many Americans are still hesitant to be vaccinated. This two-part study first experimentally tests two message frames (inoculation vs control) designed to counter resistance to the COVID-19 vaccine with individuals who are initially supportive, neutral or opposed to it. Based on a key finding from Study 1 (that political ideology appears to be impacting receptiveness to the messaging), Study 2 examines response to these same two messages using either a politicized (Dr. Anthony Fauci) or neutral source to test the mediating effects of political ideology. Results contribute to existing literature by examining inoculation effects in a new context (“debunking” misinformation vs “prebunking” to bolster supportive attitudes), and demonstrate how psychological reactance is working in tandem with inoculation to influence attitudes toward the COVID-19 vaccine.