Development of vaccine formulations: past, present, and future

Abstract

The current situation, heavily influenced by the ongoing pandemic, puts vaccines back into the spotlight. However, the conventional and traditional vaccines present disadvantages, particularly related to immunogenicity, stability, and storage of the final product. Often, such products require the maintenance of a "cold chain," impacting the costs, the availability, and the distribution of vaccines. Here, after a recall of the mode of action of vaccines and the types of vaccines currently available, we analyze the past, present, and future of vaccine formulation. The past focuses on conventional formulations, the present discusses the use of nanoparticles for vaccine delivery and as adjuvants, while the future presents microneedle patches as alternative formulation and administration route. Finally, we compare the advantages and disadvantages of injectable solutions, nanovaccines, and microneedles in terms of efficacy, stability, and patient-friendly design. Different approaches to vaccine formulation development, the conventional vaccine formulations from the past, the current development of lipid nanoparticles as vaccines, and the near future microneedles formulations are discussed in this review.

Keywords: Drug delivery; Immunotherapy; Microneedles; Nanoparticles; Vaccination.

Fig. 1

Immune activation after vaccination. The antigens and adjuvants contained in the vaccine formulation are taken-up by immature APC or B cell. The APC processes the signal and achieves a mature phenotype, further transmitting the signal to cytotoxic T cells, helper T cells, and B cells. The endpoint in a successful vaccination is the development of antigen-specific antibodies and cytotoxic T cells. Figure created from elements of Servier Medical Art, licensed under a Creative Commons Attribution 3.0 Unported License

Fig. 2

Mode of action of antibodies against viruses. The seven different mechanisms by which antibodies can block a viral infection (the examples in the figure refers to flu). Reproduced with permission from ref. [14]

Fig. 3

Classes of vaccines, their main advantages, and disadvantages. Figure created from elements of Servier Medical Art, licensed under a Creative Commons Attribution 3.0 Unported License

Fig. 4

Stability of common vaccines to freeze and heat stress in ordinal scale. a Conventional vaccines. b Vaccines newly introduced in clinical practice. BCG Bacille Carmen Guerin, DTP diphtheria–tetanus–pertussis, Hep A hepatitis A, HepB hepatitis B, OPV oral poliomyelitis vaccine, Hib: Haemophilus influenza type b, HPV human papilloma virus, IPV inactivated polio vaccine, JE Japanese encephalitis, Men A meningitis A, Men PS meningitis polysaccharide, MMR measles–mumps–rubella, Penta DTP + HepB + Hib, Rotarix® and Rotateq® rotavirus vaccine, TT tetanus toxoid, Typhim Vi® typhoid polysaccharide vaccine Reproduced from ref. [38], under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0)

Fig. 5

Internalization pathway of nanoparticles. a Side view of the internalization pathway for PEGylated nanoparticles with grafting density 1.6 chains per nm². b Top view of the internalization pathway for PEGylated nanoparticles with grafting density 0.6 chains per nm². Reprinted with permission from ref. [59]

Fig. 6

Mode of action of SAPN NPs. SAPN adjuvanted with glucopyranosyl lipid adjuvant–stable emulsion (GLA-SE) has peptides that are presented by MHC molecules on the follicular dendritic cells to T lymphocytes. Reprinted with permission from Ref. [77]

Fig. 7

Possible benefits of MN vaccine implementation in developing countries

Fig. 8

MNs for influenza vaccination. a MNs contain an array of 100 MNs measuring 650 μm tall that is mounted on an adhesive backing. b MNs are manually administered to the wrist, enabling self-administration by study participants Reproduced with permission from Ref. [107]

Fig. 9

Solicited reports of adverse events 7 days after vaccination and serological response to study drug administration. a Local and systemic adverse events associated with vaccination are shown in different groups. IIV inactivated influenza vaccine, 7 days after vaccination, MNP microneedle patch, HCW health-care worker, IM intramuscular. b Hemagglutination inhibition GMTs (log 2), seroconversion, and seroprotection against A/Christchurch/16/2010 (NIB-74 [H1N1]), A/Texas/50/2012 (NYMC X-223 [H3N2]), and B/Massachusetts/2/2012 (NYMC BX-51[B]) strains for MNP_IIV-HCW, MNP_IIV-self, MNP_placebo, and IM_IIV 28 days after vaccination. Bars show 95% CI. GMT geometric mean titers, IIV inactivated influenza vaccine, MNP microneedle patches, HCW health care worker, IM intramuscular Reproduced with permission from ref. [107]