Various types of vaccines are under pre-clinical and clinical development to address the recent appearance of Middle East respiratory syndrome or MERS, an emerging infectious disease that has already caused over 600 deaths and remains a threat to world health. The causative agent for this respiratory disease is a member of the betacoronavirus genus, phylogenetically closely related to the SARS coronavirus that caused an international health emergency in 2002. With lessons learned from the outbreak of severe acute respiratory syndrome, and with undeniable technological advances, vaccine development against MERS was initially fast-paced and has produced several DNA and protein vaccine candidates with promising results during early pre-clinical testing. At least one vaccine candidate has even entered first-in-humans clinical trials now. With the number of MERS cases declining though and other infectious diseases attracting increased attention, the question remains, whether, similar to the situation after the SARS pandemic, vaccine development is halted or remains the priority it rightfully should.
In 2017, the World Health Organization (WHO) named A. baumannii as one of the three antibiotic-resistant bacterial species on its list of global priority pathogens in dire need of novel and effective treatment. With only polymyxin and tigecycline antibiotics left as last-resort treatments, the need for novel alternative approaches to the control of this bacterium becomes imperative. Vaccines against numerous bacteria have had impressive records in reducing the burden of the respective diseases and addressing antimicrobial resistance; as in the case of Haemophilus influenzae type b . A similar approach could be appropriate for A. baumannii. Toward this end, several potentially protective antigens against A. baumannii were identified and evaluated as vaccine antigen candidates. A licensed vaccine for the bacteria, however, is still not in sight. Here we explore and discuss challenges in vaccine development against A. baumannii and the promising approaches for improving the vaccine development process.
The ten member states of the Association of Southeast Asian Nations (ASEAN) constitute an economic powerhouse, yet these countries also harbor a mostly hidden burden of poverty and neglected tropical diseases (NTDs). Almost 200 million people live in extreme poverty in ASEAN countries, mostly in the low or lower middle-income countries of Indonesia, the Philippines, Myanmar, Viet Nam, and Cambodia, and many of them are affected by at least one NTD. However, NTDs are prevalent even among upper middle-income ASEAN countries such as Malaysia and Thailand, especially among the indigenous populations. The three major intestinal helminth infections are the most common NTDs; each helminthiasis is associated with approximately 100 million infections in the region. In addition, more than 10 million people suffer from either liver or intestinal fluke infections, as well as schistosomiasis and lymphatic filariasis (LF). Intestinal protozoan infections are widespread, while leishmaniasis has emerged in Thailand, and zoonotic malaria (Plasmodium knowlesi infection) causes severe morbidity in Malaysia. Melioidosis has emerged as an important bacterial NTD, as have selected rickettsial infections, and leptospirosis. Leprosy, yaws, and trachoma are still endemic in focal areas. Almost 70 million cases of dengue fever occur annually in ASEAN countries, such that this arboviral infection is now one of the most common and economically important NTDs in the region. A number of other arboviral and zoonotic viral infections have also emerged, including Japanese encephalitis; tick-borne viral infections; Nipah virus, a zoonosis present in fruit bats; and enterovirus 71 infection. There are urgent needs to expand surveillance activities in ASEAN countries, as well as to ensure mass drug administration is provided to populations at risk for intestinal helminth and fluke infections, LF, trachoma, and yaws. An ASEAN Network for Drugs, Diagnostics, Vaccines, and Traditional Medicines Innovation provides a policy framework for the development of new control and elimination tools. Together with prominent research institutions and universities, the World Health Organization (WHO), and its regional offices, these organizations could implement important public health improvements through NTD control and elimination in the coming decade.
Middle East respiratory syndrome coronavirus (MERS-CoV) has infected at least 2040 patients and caused 712 deaths since its first appearance in 2012, yet neither pathogen-specific therapeutics nor approved vaccines are available. To address this need, we are developing a subunit recombinant protein vaccine comprising residues 377-588 of the MERS-CoV spike protein receptor-binding domain (RBD), which, when formulated with the AddaVax adjuvant, it induces a significant neutralizing antibody response and protection against MERS-CoV challenge in vaccinated animals. To prepare for the manufacture and first-in-human testing of the vaccine, we have developed a process to stably produce the recombinant MERS S377-588 protein in Chinese hamster ovary (CHO) cells. To accomplish this, we transfected an adherent dihydrofolate reductase-deficient CHO cell line (adCHO) with a plasmid encoding S377-588 fused with the human IgG Fc fragment (S377-588-Fc). We then demonstrated the interleukin-2 signal peptide-directed secretion of the recombinant protein into extracellular milieu. Using a gradually increasing methotrexate (MTX) concentration to 5 μM, we increased protein yield by a factor of 40. The adCHO-expressed S377-588-Fc recombinant protein demonstrated functionality and binding specificity identical to those of the protein from transiently transfected HEK293T cells. In addition, hCD26/dipeptidyl peptidase-4 (DPP4) transgenic mice vaccinated with AddaVax-adjuvanted S377-588-Fc could produce neutralizing antibodies against MERS-CoV and survived for at least 21 days after challenge with live MERS-CoV with no evidence of immunological toxicity or eosinophilic immune enhancement. To prepare for large scale-manufacture of the vaccine antigen, we have further developed a high-yield monoclonal suspension CHO cell line.