Prime-boost vaccine strategy against viral infections: Mechanisms and benefits

The essential goal of vaccination is to generate potent and long-term protection against diseases. Among different vaccine modalities, prime-boost vaccine strategies could enhance cellular and also humoral immunity in several animal models. These strategies have been applied for the development of vaccines against important infectious diseases such as HIV, SIV, HCV, HSV, and HBV indicating promising results even in clinical trials. Several factors including selection of antigen, type of vector, delivery route, dose, adjuvant, boosting regimen, the order of vector injection, and the intervals between different vaccinations influence the outcome of prime-boost immunization approaches. The reported data suggest that the prime-boost strategy as a combination of vaccines (i.e., heterologous prime-boost) may be better than a single vaccine for protection against infectious diseases. Indeed, in many cases, heterologous prime-boost can be more immunogenic than homologous prime-boost strategy. This review discusses the recent advances in prime-boost immunization strategies as well as their benefits and mechanisms of action.     

Vaccination against HPV: boosting coverage and tackling misinformation

The availability of human papillomavirus (HPV) vaccines and screening tests has raised the possibility of globally eliminating cervical cancer, which is caused by HPV. Cervical cancer is a very common malignancy worldwide, especially among deprived women. High vaccination coverage is key to the containment and eventual elimination of the infection. Public HPV vaccination programmes in Italy and Denmark were swiftly established and are among the most successful worldwide. Still, in both countries, it has been challenging to achieve and maintain the recommended coverage of > 80% in girls. In a well‐studied Italian region, vaccination coverage in girls at age 15 years (World Health Organization''s gold standard) reached 76% in 2015 but decreased to 69% in 2018, likely due to work overload in public immunization centres. In Denmark, doubts about safety and efficacy of the HPV vaccine generated a decline in coverage among girls age 12–17, from 80% in 2013 down to 37% in 2015, when remedial actions made it rise again. Insights from these two countries are shared to illustrate the importance of monitoring coverage in a digital vaccine registry and promptly reacting to misinformation about vaccination.

Abbreviations

CC

cervical cancer

FVG

Friuli Venezia Giulia

HICs

high‐income countries

HPV

human papillomavirus

LMICs

middle‐income countries

WHO

World Health Organization

     

Humoral and Cellular Responses to Influenza Vaccination in Human Recipients Naturally Tolerant to a Kidney Allograft

Rare kidney allograft recipients enjoy unaltered graft function years after interruption of their immunosuppressive treatment. To assess the extent to which this state of 'operational tolerance' (TOL) is specific to the graft and not the result of a global immunodeficiency, we analyzed the response of such patients following influenza vaccination. Hemagglutination inhibition titers and frequency of IFNgamma-secreting T cells were measured before 1 and 3 months after vaccination. The proportion of healthy volunteers (HV) responding to vaccine was significantly higher than that of immunosuppressed (IS) patients. Three 'TOL' patients presented a humoral response similar to that of HV, whereas the two others had a poor response, like the IS recipients. Although the small number of patients does not allow for definitive conclusions to be made, these data suggest that the status of tolerance may be heterogeneous, with some patients with a global immunodeficiency and others with an adapted response to vaccination.     

The role of infection and vaccination in the genesis of optic neuritis and multiple sclerosis in children

This article describes the association between previous infection and/or vaccination and the development of optic neuritis (ON) in 18 children. Ten of these children subsequently developed clinically definite multiple sclerosis (MS), while in 8 patients a clinically definite etiology could not be confirmed. Vaccination preceded the first ON attack in 6 patients, all but one of whom subsequently developed MS. It also preceded subsequent demyelinating events in 6 patients. Ten of the patients had a bacterial or viral infection within the 2 weeks prior to the first symptoms of ON. Intrathecal antibody synthesis against 2 or more viruses could be shown in 5 out of 8 patients studied; 5 out of 6 patients had oligoclonal antibodies in CSF and 12 out of 16 patients a high IgG index. Neither intrathecal antibody synthesis against 2 or more viruses nor elevated IgG indexes could be found in the control patients. Measles and mumps occurred at a significantly later age in the children who subsequently developed MS than in the control children, and these patients had significantly more events that might have impaired the blood-brain barrier than the controls. These results indicate that immunological events leading to MS may be triggered during childhood. Vaccination and infection often precede ON in childhood. Intrathecal viral antibody production can occur already in childhood at the time of the first symptoms of MS.     

Granuloma annulare possibly triggered by antitetanus vaccination

We report the case of a 6-year-old girl with granuloma annulare (GA) possibly related to antitetanus vaccinations. The first episode occurred 2 months after the girl had been vaccinated but the lesions were not located at the vaccination site. After 1 year of being free of lesions, she had a second episode unrelated to vaccination. After another 6-month lesion-free period, the girl was administered another antitetanus vaccination and a solitary lesion developed at the vaccination site within 3 days. A few lesions developed on her legs in the 2 months following the appearance of the initial plaque. The literature includes two reports of cases with papular lesions limited to the hepatitis B vaccination site, both histopathologically consistent with necrobiotic granuloma, but clinically not suggestive of GA. To the best of our knowledge, GA following antitetanus vaccination and occurring at the vaccination site has not been reported before. Either the trauma alone from the injection or a vaccine-induced immunological reaction might have triggered the necrobiosis of collagen through some unexplained mechanisms.     

Immunogenicity and safety of a novel yeast Hansenula polymorpha-derived recombinant Hepatitis B candidate vaccine in healthy adolescents and adults aged 10–45 years

The aim was to determine whether the immunogenicity of an investigational hepatitis B vaccine (spHB) is at least as high as that of a licensed control vaccine, Engerix B^®, and to evaluate its safety before inclusion in new pediatric combination vaccines. Two randomized, controlled, blind-observer, Phase 3 trials were performed: one in Argentina (344 participants aged 10–15 years, 10 μg HBsAg/dose) and one in Uruguay (344 participants aged 16–45 years, 20 μg HBsAg/dose). Both vaccines were given in a 0, 1, 6 month schedule to all participants with a baseline anti-Hep B antibody titer <0.6 mIU/mL. Antibody titers were measured pre-dose 1, 1 month after dose 2, pre-dose 3, and 1 month after dose 3. Statistical non-inferiority analyses were performed on seroprotection rates (SP) post-dose 3 (% with anti-Hep B titers ≥10 mIU/mL; delta non-inferiority limit of −10%). In both studies, SP for the spHB vaccine was 100% and the spHB vaccine was non-inferior in terms of SP to the licensed control vaccine. GMTs post-dose 3 were approximately 1.8- and 4.1-fold higher for spHB in the 10–15 year and 16–45 year age groups, respectively. Reactogenicity was low for each vaccine, after each dose. This highly immunogenic hepatitis B candidate vaccine was selected for further investigation as a component of new pediatric combination vaccines.     

Priming with a very low dose of DNA complexed with cationic block copolymers followed by protein boost elicits broad and long-lasting antigen-specific humoral and cellular responses in mice

Cationic block copolymers spontaneously assemble via electrostatic interactions with DNA molecules in aqueous solution giving rise to micellar structures that protect the DNA from enzymatic degradation both in vitro and in vivo. In addition, we have previously shown that they are safe, not immunogenic and greatly increased antigen-specific CTL responses following six intramuscular inoculations of a very low dose (1 μg) of the vaccine DNA as compared to naked DNA. Nevertheless, they failed to elicit detectable humoral responses against the antigen. To gain further insight in the potential application of this technology, here we show that a shorter immunization protocol based on two DNA intramuscular inoculations of 1 μg of DNA delivered by these copolymers and a protein boost elicits in mice broad (both humoral and cellular) and long-lasting responses and increases the antigen-specific Th1-type T cell responses and CTLs as compared to priming with naked DNA. These results indicate that cationic block copolymers represent a promising adjuvant and delivery technology for DNA vaccination strategies aimed at combating intracellular pathogens.     

Genetic immunization with GPI-anchored anthrax protective antigen raises combined CD1d- and MHC II-restricted antibody responses by natural killer T cell-mediated help

Studies have demonstrated that lipid rafts ultimately regulate the endocytosis of anthrax toxin via clathrin dependent pathway. Interestingly, GPI-anchored protein rich rafts have also been shown to be transported down to the endocytic pathway to reducing late endosomes. Taking advantage of this parallelism, we tried translating the anthrax toxin natural intoxication mechanism by administering a DNA chimera that encoded protective antigen attached to a mammalian GPI-anchor sequence at its C-terminus (pGPI-PA63). We also designed a chimera that had an additional N-terminal TPA leader sequence (pTPA.GPI-PA63) with an aim to target GPI-PA63 to ER where new CD1 molecules are synthesized. Analysis of antibody titers demonstrated successful priming and potential IgG titers after the first boost. In vitro cell proliferation studies in the presence of GPI-attached PA63 peptides revealed that there was a clonal expansion of CD4⁺ NK1.1⁺ helper T cell population which rapidly produced IL-4 in response to T cell receptor ligation. These cells provided direct B cell help that aided IgG formation. Effector responses generated by NKT cells were found to be MHC II-independent and CD1d-restricted. In addition, the group pTPA.GPI-PA63 also displayed low magnitude MHC-II restricted (CD1d-independent) NKT cell and CD4⁺ T cell helper responses in response to non-GPI attached PA63 peptides which overall resulted in the heightened responses seen for this group. Importantly, DNA vaccination mediated the generation of high avidity neutralizing antibodies that mediated protection against lethal toxin challenge.