Novel antigen delivery systems

Table 1 Overview of the different vaccine formulations

Vaccine type	Description	Advantages	Disadvantages	Immunogenicity	Examples
Live attenuated vaccines	Living weakened microbes that generally show reduced pathogenicity	Induce a protective immune response by activating both B and T cell responses; induce long-term immunity; do not require adjuvants; unable to spread and cause infection	They can revert towards virulent forms or can be insufficiently attenuated for immunosuppressed individuals with risk of infection; difficult to produce in a scalable setting; heat-labile; quality and safety requirements	Humoral and cytotoxic immune responses	Smallpox; yellow fever; rabies; measles; mumps; rubella; typhoid; influenza; rotavirus; varicella
Killed/inactivated vaccines	Bacteria (killed vaccines) or viruses (inactivated vaccines) inactivated by chemical orphysical treatments	Due to the absence of living pathogens they do not revert towards virulent forms and can be used in immunodeficient hosts; not heat-labile	Repeated booster shots and adjuvants (with subsequent local reactions at the vaccine site) are required to optimally trigger the adaptive immune system and generate long-term immunity; do not give rise to cytotoxic T cells; poor induction of mucosal immunity; difficult to produce in a scalable setting; quality and safety requirements	Humoral immunity	Diphtheria; tetanus; pertussis; haemophilus influenzae type b; poliomyelitis; rabies; meningitidis; Japanese encephalitis; cholera; hepatitis A; hepatitis B
Toxoids vaccines	Purified exotoxins chemically inactivated into toxoids that retain the ability to induce toxin-neutralizing antibodies	Safe and stable. There is no possibility of reversion to pathogenicity or spread of live microbe to other animals	Poorly immunogenic; need adjuvants and large amounts or multiple doses to ensure efficient activation of the adaptive immune response and generation of long-last immunity; local reactions at vaccine site	B cell activation (T cell dependent)	Diphtheria, tetanus, and pertussis toxoids; acellular pertussis vaccines; anthrax secreted proteins
Subunit/polysaccharide vaccines	Antigenic components of pathogens: partly or fully purified protein antigens or capsular polysaccharides	Can be chemically linked to protein carrier	Variable degree of immunogenicity; need adjuvants (and often multiple doses); frequent local reactions at the injection site	T-dependent and/or T-independent immune responses	Hepatitis B and Haemophilus influenzaetype b; influenza; meningococcus, pneumococcus, and Haemophilus influenzae type B polysaccharides
Plasmid DNA	Genetically engineered vectors expressing antigens of interest	Inability to revert to pathogenic forms; activation of innate and adaptive immune responses; highly stable; easy storage and transport; large-scale production; optimization of plasmids and transcript is possible	Not-useful for non-protein immunogens; lower immunogenicity in human compared to mice; low transfection efficiency	Activation of antigen-specific B cells, CD4+ and CD8+ T cells	Infectioushaematopoieticnecrosis virus; West Nile virus; melanoma; growth hormonereleasing hormone
Vectored vaccines	Live recombinant viral and bacterial vectors expressing heterologous antigens	Ability to induce specific humoral and cellular immune responses; high transduction efficiency; highly effective in dividing and non-dividing cells; production of high levels of antigens inside target cells; sustained gene expression; vector itself can provide an adjuvant effect	High expense; toxic side effects; limits on transgene size; potential for insertional mutagenesis; anti-vector immunity; difficult to manufacture and store	B cell, CD4+ and cytotoxic CD8+ T cell activation	Adenovirus; adeno-associated virus; retrovirus; lentivirus; Herpes simplex virus; Salmonella
Nanoparticles	Nano-scale size materials made of polymers, proteins or lipids used as carrier systems (e.g., PLGA, liposomes, virosomes, Virus-like particles)	Ability to induce humoral and cellular immune responses; increased antigen uptake, processing and presentation; controlled/sustained release of vaccine target; depot effect; targeted delivery; adjuvanticity; high encapsulation; improved cargo bioavailability; transport efficiency;	Challenges in vaccine formulation, production, stabilization. Immunotoxicity can occur	B-cell, CD4+ and cytotoxic T-cell responses	Hepatitis A virus; influenza; human papilloma virus; hepatitis B virus; hepatitis E virus
		enhanced permeability; biodegradability and biocompatibility

Table 2 Preclinical studies based on E2 formulations

E2 construct	Description	Route	Immune response	Ref.
Gag(p17)-E2	HIV-1 Gag p17 matrix protein	sc	Mice immunized with Gag(p17)-E2 mounted a strong and sustained Ab response; the isotype of induced Abs was biased toward IgG1; CD8+ T cells primed with E2 particles were able to exert lytic activity and to produce IFN-γ	[65]
BS1-E2	Mimotope 1 from HIV-1 bridging sheet domain (BS)	IM1/sc1	The E2-BS1 fusion peptide showed good antigenic results; a moderate neutralizing antibody response was found against two HIV-1 clade B and one clade C primary isolates	[67]
Env(V3)-E2	HIV-1 SF162 Env V3 loop peptide 291-336 from gp120 (HXB2 numbering)	Env-E2: IM1;pDNA2: ID1	Env(V3)-E2 induced potent binding Ab and T-cell responses in mice, as well as autologous NAbs in rabbits, when co-immunized with pDNA; co-immunization with pDNA and E2 multimers generated potent immune responses after only two immunizations	[19]
Env(MPER)-E2	HIV-1 SF162 Env MPER peptide 649-689 from gp41 (HXB2 numbering)	Env-E2: IM1;pDNA23: ID1	MPER (membrane proximal external region) displayed on E2 focused Ab responses toward conserved region of HIV-1 Envelope when co-administered with pDNA lacking hypervariable loop regions	[66]
(1-11)-E2	Peptide 1-11 of beta-amyloid	sc	(1-11)E2 vaccine induced fast-rising, robust and persistent Ab responses to beta-amyloid; the Ab response was characterized by a marked prevalence of IgG1 over the IgG2a isotype	[68,69]

¹Routes of administration for rabbit immunizations;

²pDNA: codon-optimized HIV-1 SF162 plasmid DNA encoding gp160 full-length;

³Lacking hypervariable regions. sc: Subcutaneous; IM: Intramuscular; ID: Intradermal administration; Env: Envelope; gp: Glycoprotein; Ab: Antibody; NAbs: Neutralizing antibodies.