Immunogenicity and Safety of a Tetravalent Recombinant Subunit Dengue Vaccine in Adults Previously Vaccinated with a Live Attenuated Tetravalent Dengue Vaccine: Results of a Phase-I Randomized Clinical Trial

Abstract

New dengue vaccines are needed to prevent this globally expanding vector-borne disease. The V180 vaccine candidate consists of four recombinant, soluble, dengue virus envelope glycoproteins and has been previously evaluated in two clinical trials for safety and immunogenicity in Flavivirus-naive participants (NCT01477580 and NCT0093642). Here, we report on a randomized, placebo-controlled, double-blind study of the safety and immunogenicity of the V180 vaccine in subjects who have previously received the live attenuated tetravalent vaccine (LATV) developed by the National Institute of Allergy and Infectious Diseases (protocol #V180-002 [CIR-301]). The study was designed to evaluate whether this recombinant subunit vaccine could boost the neutralizing antibody responses induced by dengue LATV. Twenty participants who had previously received one or two doses of dengue LATV were randomized and received a single dose of V180 nonadjuvanted (N = 8), V180 adjuvanted with Alhydrogel™ (aluminum hydroxide gel, Brenntag Biosector, Frederikssund, Denmark) (N = 8), or placebo (N = 4). Immunogenicity was measured using a plaque reduction neutralization test at days 1, 15, 28, and 180 after vaccination. In addition, vaccine safety (solicited and unsolicited adverse events) was assessed using a vaccination report card for 28 days following vaccination, and serious adverse events were captured from the time of informed consent through the final study visit at 6 months after vaccination. The results of the study demonstrate that the V180 vaccine is generally well tolerated and immunogenic in these dengue-seropositive volunteers.

Aluminium adjuvants versus placebo or no intervention in vaccine randomised clinical trials: a systematic review with meta-analysis and Trial Sequential Analysis

“…The 102 included trials were published between 1969 and 2021; 35 were conducted in the USA;46–80 13 in more than one country;81–94 6 in Canada;95–100 4 in China;101–104 4 in Belgium;105–108 4 in Africa;109–112 3 each in the UK,113–115 Taiwan116–118 and Australia;119–121 2 each in Thailand,122 123 Poland,124 125 Norway,126 127 Italy,128 129 Germany,92 130 Cuba,131 132 and Austria;133 134 and 1 each in Switzerland,135 Sweden,136 Singapore,137 Mali,138 Israel,139 India,140 France,141 Colombia,142 Chile and Bangladesh 143. Three trials did not report a country 144–146…”

“…The included trials assessed different types of aluminium adjuvants: aluminium hydroxide (38 trials);49 50 57 59 67–70 72 74 81–83 88–90 92 93 96 101–103 105 106 110 112 114 118 122–124 126 133 134 140–142 144 aluminium phosphate (26 trials);46 47 53 60 62 63 66 75 80 86 87 97 108 109 111 115–117 121 131 132 136 139 145 146 149 alhydrogel (21 trials);48 51 52 54–56 58 73 76–79 98–100 107 113 120 125 127 137 amorphous aluminium hydroxyphosphate sulfate (2 trials);64 71 aluminium fluoride (1 trial);94 phosphate-treated aluminium hydroxide (1 trial);143 alhydrogel pretreated with phosphate buffer (1 trial);135 Adju-Phos (aluminium phosphate gel) (1 trial);95 aluminium potassium sulfate (1 trial);65 aluminium chloride (1 trial)61 and aluminium oxide (1 trial) 150. Eight trials did not describe the type of aluminium adjuvant used 84 85 91 104 128–130 138…”

“…The included trials assessed the effects of vaccines against different viruses, bacteria, toxins or diseases: influenza (25 trials);49 50 54 56 67 68 84 88 98–100 102 104 115 117 118 121 126 130 133 137 139–141 150 Streptococcus pneumoniae (11 trials);74 85–87 94 108 111 135 143 145 146 respiratory syncytial virus (11 trials);60 62 63 79 80 82 96 97 105 119 144 human immunodeficiency virus (6 trials);47 59 75 110 128 129 Neisseria meningitidis (6 trials);53 61 66 109 127 138 Clostridium difficile (4 trials);57 69 78 83 dengue fever virus (4 trials);55 58 120 151 enterovirus (3 trials);101 103 116 Bacillus anthracis (3 trials);48 51 52 diphtheria and tetanus (2 trials);113 136 human papillomavirus (2 trials);65 72 Lyme borreliosis (2 trials);89 93 Haemophilus influenzae type B (2 trials);131 132 group B Streptococcus (2 trials);76 107 Staphylococcus aureus (2 trials);64 71 poliovirus (2 trials);124 125 Pseudomonas aeruginosa (2 trials);90 92 Alzheimer’s disease (2 trials);91 134 cytomegalovirus (2 trials);46 95 tetanus (1 trial);114 non-typeable Haemophilus influenzae (1 trial);107 Ross River virus (1 trial);81 hepatitis B (1 trial);112 malaria (1 trial);142 rabies and tetanus (1 trial);122 rabies (1 trial);123 Shigella flexneri (1 trial)77 and S. aureus and Candida albican s (1 trial) 73…”

“…The included trials administered different numbers of vaccine doses: 24% of the trials administered 1 dose;53 55 58 60 64 66 70 73 76 82 87 96 97 100 107 111 114 124 131 133 136 139 140 150 40% of the trials administered two doses;49–52 54 56 61–63 67 68 75 77 79 80 84 88 90 92 98 99 101–105 108 109 115–119 121 126 127 130 135 137 138 141 146 21% of the trials administered three doses;46 47 57 59 65 71 72 74 78 81 85 89 95 106 110 112 113 120 123 125 132 142 143 10% of the trials administered four doses;69 83 86 93 94 134 145 two trials administered five doses128 129 and one trial administered seven doses 91. Two trials did not specify the number of doses administered 122 144…”

Adjuvants Differentially Modulate the Immunogenicity of Lassa Virus Glycoprotein Subunits in Mice

“…Expression of antigens in stably transformed Drosophila S2 cell lines requires less stringent culturing conditions than mammalian cell lines while using immunoaffinity chromatography for purification can significantly improve purity, thereby reducing the number of required purification steps and reducing production costs (58,59). Insect cell-derived viral surface glycoproteins formulated with adjuvant have a good safety and immunogenicity record in clinical trials (61)(62)(63)(64).…”