Multi-Dose Formulation Development for a Quadrivalent Human Papillomavirus Virus-Like Particle-Based Vaccine: Part I - Screening of Preservative Combinations

Jerajani, Kaushal; Wan, Ying; Kumru, Ozan S.; Pullagurla, Swathi R.; Kumar, Prashant; Sharma, Nitya; Ogun, Oluwadara; Mapari, Shweta; Brendle, Sarah A.; Christensen, Neil D.; Batwal, Saurabh; Mahedvi, Mustafa; Rao, Harish; Dogar, Vikas; Chandrasekharan, Rahul; Shaligram, Umesh; Joshi, Sangeeta B.; Volkin, David B.

doi:10.1016/j.xphs.2022.09.001

Cited by 5 publications

(11 citation statements)

References 30 publications

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“…Finally, an important emphasis of future formulation optimization work with adjuvanted IVX-411 would include lowering costs to improve access for use in LMICs. Examples include lowering raw material and primary packaging costs (e.g., excipients, adjuvant, vials, stoppers), improving vaccine stability in the cold chain (e.g., vaccine vial monitor, VVM, designation), 9 and developing multidose (more doses per vial) 68 , 69 and combination vaccine (more vaccines per dose) 70 formulations.…”

Section: Discussionmentioning

confidence: 99%

Effects of aluminum-salt, CpG and emulsion adjuvants on the stability and immunogenicity of a virus-like particle displaying the SARS-CoV-2 receptor-binding domain (RBD)

Kumru,

Bajoria,

Kaur

et al. 2023

Human Vaccines & Immunotherapeutics

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Second-generation COVID-19 vaccines with improved immunogenicity (e.g., breadth, duration) and availability (e.g., lower costs, refrigerator stable) are needed to enhance global coverage. In this work, we formulated a clinical-stage SARS-CoV-2 receptor-binding domain (RBD) virus-like particle (VLP) vaccine candidate (IVX-411) with widely available adjuvants. Specifically, we assessed the in vitro storage stability and in vivo mouse immunogenicity of IVX-411 formulated with aluminum-salt adjuvants (Alhydrogel™, AH and Adjuphos™, AP), without or with the TLR-9 agonist CpG-1018™ (CpG), and compared these profiles to IVX-411 adjuvanted with an oil-in-water nano-emulsion (AddaVax™, AV). Although IVX-411 bound both AH and AP, lower binding strength of antigen to AP was observed by Langmuir binding isotherms. Interestingly, AH- and AP-adsorbed IVX-411 had similar storage stability profiles as measured by antigen-binding assays (competitive ELISAs), but the latter displayed higher pseudovirus neutralizing titers (pNT) in mice, at levels comparable to titers elicited by AV-adjuvanted IVX-411. CpG addition to alum (AP or AH) resulted in a marginal trend of improved pNTs in stressed samples only, yet did not impact the storage stability profiles of IVX-411. In contrast, previous work with AH-formulations of a monomeric RBD antigen showed greatly improved immunogenicity and decreased stability upon CpG addition to alum. At elevated temperatures (25, 37°C), IVX-411 formulated with AH or AP displayed decreased in vitro stability compared to AV-formulated IVX-411and this rank-ordering correlated with in vivo performance (mouse pNT values). This case study highlights the importance of characterizing antigen-adjuvant interactions to develop low cost, aluminum-salt adjuvanted recombinant subunit vaccine candidates.

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Section: Discussionmentioning

confidence: 99%

Effects of aluminum-salt, CpG and emulsion adjuvants on the stability and immunogenicity of a virus-like particle displaying the SARS-CoV-2 receptor-binding domain (RBD)

Kumru,

Bajoria,

Kaur

et al. 2023

Human Vaccines & Immunotherapeutics

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“…50–52 Each of these IPV-containing combination vaccines also contain diphtheria, tetanus, and acellular pertussis antigens, while some newer ones also include Hepatitis B and Haemophilus influenzae type b. Notably, none of these US FDA and WHO prequalified IPV containing combination vaccines contain whole-cell pertussis (wP) and none are available in multidose formats (i.e., single-dose presentations contain one vaccine dose per vial, while multi-dose typically contain 2 to 10 vaccine doses in single vial to reduce cost and improve vaccine coverage; 54 see next section). The reported shelf-life values of the commercially available IPV containing combination vaccines are 3 to 3.5 years at 2–8°C, although this information has not been disclosed for some products ( Table 3 ).…”

Section: Commercially Available Ipv and Sipv Vaccine Formulationsmentioning

confidence: 99%

“…Although single-dose vials and prefilled syringes are a convenient method to deliver intramuscularly injected IPV vaccines, they cost more to manufacture, take up more space in the vaccine cold chain, and create more medical waste compared to multi-dose formulations. 54 , 59 Multi-dose formulations allow for multiple vaccine doses to be obtained from a single vial by inserting multiple needles into the same vial. To prevent potential bacterial contamination, multi-dose IPV vaccines are formulated with antimicrobial preservatives (APs).…”

Section: Low-cost and Next-generation Ipv Vaccine Formulationsmentioning

confidence: 99%

“…In contrast, different HPV vaccines (consisting of HPV VLP antigens from unique expression systems, purifications, and formulations) each display different stability profiles in the presence of different preservatives, a situation that has led to the requirement of customized approaches for multidose HPV vaccine formulation development. 54 , 144 Compared to standalone trivalent IPV vaccines, formulation development of multidose HPV vaccines is even more challenging since they not only contain aluminum adjuvants but also between two and nine different HPV VLP antigens with varying sensitivities to preservatives. Currently, no multidose HPV vaccines are commercially available.…”

Section: Conclusion and Applications Of Ipv/sipv Formulation Developm...mentioning

confidence: 99%

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Current and next-generation formulation strategies for inactivated polio vaccines to lower costs, increase coverage, and facilitate polio eradication

Kumar

Bird

Holland

et al. 2022

Human Vaccines & Immunotherapeutics

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Implementation of inactivated polio vaccines (IPV) containing Sabin strains (sIPV) will further enable global polio eradication efforts by improving vaccine safety during use and containment during manufacturing. Moreover, sIPV-containing vaccines will lower costs and expand production capacity to facilitate more widespread use in low- and middle-income countries (LMICs). This review focuses on the role of vaccine formulation in these efforts including traditional Salk IPV vaccines and new sIPV-containing dosage forms. The physicochemical properties and stability profiles of poliovirus antigens are described. Formulation approaches to lower costs include developing multidose and combination vaccine formats as well as improving storage stability. Formulation strategies for dose-sparing and enhanced mucosal immunity include employing adjuvants (e.g. aluminum-salt and newer adjuvants) and/or novel delivery systems (e.g. ID administration with microneedle patches). The potential for applying these low-cost formulation development strategies to other vaccines to further improve vaccine access and coverage in LMICs is also discussed.

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“…After establishing the stability-indicating nature of these assays, formulation studies were performed, including compatibility and stability assessments after mixing the t-NRRV and pentavalent vaccine antigens together in terms of alum adsorption, antibody binding, and wP immunogenicity. In addition, preservatives are also required to develop multidose formulations of such combination vaccines to further ease cost [ 25 ]. To this end, we also examined the effects of eight different preservatives on t-NRRV stability and selected promising leads for future multidose formulation development work.…”

Section: Introductionmentioning

confidence: 99%

Evaluating the Compatibility of New Recombinant Protein Antigens (Trivalent NRRV) with a Mock Pentavalent Combination Vaccine Containing Whole-Cell Pertussis: Analytical and Formulation Challenges

Kumar,

Holland,

Secrist

et al. 2024

Vaccines

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Introducing new recombinant protein antigens to existing pediatric combination vaccines is important in improving coverage and affordability, especially in low- and middle-income countries (LMICs). This case-study highlights the analytical and formulation challenges encountered with three recombinant non-replicating rotavirus vaccine (NRRV) antigens (t-NRRV formulated with Alhydrogel® adjuvant, AH) combined with a mock multidose formulation of a pediatric pentavalent vaccine used in LMICs. This complex formulation contained (1) vaccine antigens (i.e., whole-cell pertussis (wP), diphtheria (D), tetanus (T), Haemophilus influenza (Hib), and hepatitis B (HepB), (2) a mixture of aluminum-salt adjuvants (AH and Adju-Phos®, AP), and (3) a preservative (thimerosal, TH). Selective, stability-indicating competitive immunoassays were developed to monitor binding of specific mAbs to each antigen, except wP which required the setup of a mouse immunogenicity assay. Simple mixing led to the desorption of t-NRRV antigens from AH and increased degradation during storage. These deleterious effects were caused by specific antigens, AP, and TH. An AH-only pentavalent formulation mitigated t-NRRV antigen desorption; however, the Hib antigen displayed previously reported AH-induced instability. The same rank-ordering of t-NRRV antigen stability (P[8] > P[4] > P[6]) was observed in mock pentavalent formulations and with various preservatives. The lessons learned are discussed to enable future multidose, combination vaccine formulation development with new vaccine candidates.

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Multi-Dose Formulation Development for a Quadrivalent Human Papillomavirus Virus-Like Particle-Based Vaccine: Part I - Screening of Preservative Combinations

Cited by 5 publications

References 30 publications

Effects of aluminum-salt, CpG and emulsion adjuvants on the stability and immunogenicity of a virus-like particle displaying the SARS-CoV-2 receptor-binding domain (RBD)

Effects of aluminum-salt, CpG and emulsion adjuvants on the stability and immunogenicity of a virus-like particle displaying the SARS-CoV-2 receptor-binding domain (RBD)

Current and next-generation formulation strategies for inactivated polio vaccines to lower costs, increase coverage, and facilitate polio eradication

Evaluating the Compatibility of New Recombinant Protein Antigens (Trivalent NRRV) with a Mock Pentavalent Combination Vaccine Containing Whole-Cell Pertussis: Analytical and Formulation Challenges

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