PREVENTION OF HIV INFECTION THROUGH VACCINATION: RESEARCH DIRECTIONS AND LIMITS
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PREVENTION OF HIV INFECTION THROUGH VACCINATION:
RESEARCH DIRECTIONS AND LIMITS
Viorela-Ioana Nicolae1,2, Edgar-Costin Chelaru1,2, Ștefan-Decebal Guță1,2*
Costin-Ștefan Caracoti1,2, Alexandru-Andrei Muntean1,2
1
Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
2
Cantacuzino National Medico-Military Institute for Research and Development, Bucharest, Romania
ABSTRACT
Human immunodeficiency virus (HIV) is a circular retrovirus that belongs to the Lentivirus genus. Through
multiple mechanisms, the virus penetrates and replicates inside host cells, causing a chronic infection in
humans, with a long latency period and multiple pathological implications, an example being AIDS (acquired
human immunodeficiency syndrome), a serious condition that progressively destroys the body’s immune
system. There is currently no curative treatment for this infection, antiretroviral therapy (ART) being the only
control of virus replication and transmission. Although new therapies provide a longer life expectancy than
in the past, many people living with HIV remain undiagnosed or are diagnosed late. For this reason, HIV
infection is an important medical problem worldwide; the latest research in this field aiming at developing a
vaccine intended to prevent HIV infection.
This review follows some of the current studies aimed to prevent HIV infection through vaccination and
the limits encountered in their development. At the end of the paper some promising directions for the future
of this field are presented.
Keywords: HIV, prevention, vaccine, viral vector, human monoclonal antibody, DNA
REZUMAT
Virusul imunodeficienței umane (HIV) este un retrovirus circular ce face parte din genul lentivirusurilor.
Prin multiple mecanisme virusul pătrunde și se replică în interiorul celulelor gazdă, provocând la om o infecție
cronică cu o perioadă lungă de latență și multiple implicații patologice, un exemplu fiind SIDA (sindromul
imunodeficienței umane dobândite), o afecțiune gravă ce distruge progresiv sistemul imun al organismului.
În prezent nu există un tratament curativ pentru această infecție, terapia antiretrovirală (ART) fiind singura
formă de controlare a replicării și transmiterii virusului. Deși noile terapii asigură o speranță de viață mai
lungă decât în trecut, multe persoane care trăiesc cu HIV rămân nediagnosticate sau sunt diagnosticate târziu.
Din acest motiv, infecția HIV este o problemă medicală importantă la nivel mondial, ultimele cercetări în acest
domeniu îndreptându-se către realizarea unui vaccin ce are ca scop prevenirea infecției HIV.
În acest review sunt studiate o parte din studiile de actualitate ce au ca scop cercetarea în vederea prevenției
infectării cu virusul HIV prin vaccinare și limitele întâmpinate în urma desfășurării acestora. În finalul
articolului sunt prezentate și câteva direcții promițătoare pentru viitorul acestui domeniu.
Cuvinte-cheie: HIV, prevenire, vaccin, vector viral, anticorpi monoclonali umani, ADN
INTRODUCTION
The human immunodeficiency virus analysis it was concluded that LAV and HTLV
(HIV) is part of the Retroviridae family, III were identical and were named HIV. In 1986
genus Lentivirinae. As a clinical entity, the followed the discovery of LAV-2 or HTLV IV,
HIV infection was reported in 1981, and the which was later called HIV-2 [1-2].
etiological agent was isolated in 1983 and named Over time, various hypotheses have
Lymphadenopathy Associated Virus (LAV). emerged about the origin of the virus. The
Shortly afterwards, in 1984, a T-cytopathic human immunodeficiency virus is divided
retrovirus was isolated and grouped as HTLV into two types, called HIV-1 and HIV-2 [1].
III. Further, through cloning and sequence It has recently been shown that they emerged
* Corresponding author: Guță Ștefan-Decebal, e-mail: guta.stefan.decebal@gmail.com
ROMANIAN ARCHIVES OF MICROBIOLOGY AND IMMUNOLOGY, Volume 79, Issue 3, pp 195-208 July-September 2020 195NICOLAE et al. naturally, being transmitted from primates to response) [1, 6]. humans. Molecular tests were able to compare From an epidemiological point of view, human immunodeficiency viruses and similar HIV-1 is responsible for 95% of infections in simian viruses, as well as their phylogeny. the world and includes 4 groups: M, the major Initially, the results showed that HIV-2 came group, and N, O, P which are less common. from West Africa, from the Sooty Mangabey M group (main) comprises the viruses most monkey species, and it has subsequently been frequently involved in infections and is further proved that the most probable source for HIV-1 divided into subtypes: A1, A2, A3, A4, A6, B, C, is a subspecies of chimpanzee, Pantroglodytes D, F1, F2, G, H, J, K. In addition, viruses from troglodytes from Central Africa [2-3]. different subtypes can combine their genetic The earliest evidence of human infection is material to form a hybrid virus, classified as a from a blood sample collected in 1959 in D.R. ‘circulating recombinant form’ (CRF). N group of the Congo, containing an HIV-1 strain [4]. (non-M, non-O) includes distinct viral strains, Considering that the virus looks like a precursor isolated from only a few people in Cameroon. to current strains of HIV in the world and the These appear to be recombinant forms between high rate of errors produced at the time of viral an HIV-like virus and an SIV-like virus, which replication, it can be estimated that the time of suggests that recombination between the two transmission from monkey to man occurred viral species and / or overcoming the species before 1940 [5]. barrier is possible, with the emergence of new HIV has a genome consisting of two identical viral types with unpredictable pathogenic single-stranded, linear, positive-sense RNA capacity. O group (outlier) is responsible for molecules. The major antigens of the viral some of the infections in Central and West envelope are gp 160 and the cleavage products, African countries or countries that had colonies gp 120 and gp 41, these being the first to come in this area. The differences from M group are into contact with the defence factors. The many, especially in the envelope and the pol mechanism through which it enters the body is gene, which encodes the reverse transcriptase, mediated by CD4+ receptors, which are present led to difficulties in diagnosis and treatment. on the surface of leukocytes, endothelial cells P group (‘pending the identification of further and gastrointestinal epithelial cells. In the human cases’) is the newest, formed in 2004. In cell, the virus envelope is formed using the 2009, its resemblance to a recently discovered host’s intracellular resources, thus integrating SIV in gorillas was pointed [3, 7-10]. some of the membrane proteins of the host cell HIV-2 is less prevalent and pathogenic such as molecules encoded by the HLA I and and comprises 8 groups marked from A to H, II genes. Also, through a peptide that binds the main ones being A and B. In this type, simultaneously to MHC II molecules and to the recombinant strains are rare; the first case of CD4 lymphocyte receptor, HIV behaves as a HIV-2 CRF was described in 2010 [9-10]. superantigen [1, 6]. Starting with the last part of the 20th century, CD4+ T-helper lymphocytes are the only HIV infection became a problem of maximum cells in which the virus replicates in high titers, importance, spreading very fast within 10 years. macrophages being also susceptible, but in In 1992, WHO data showed that 10-12 million much lower infectious titers. A major feature people were infected. According to UNAIDS of this retrovirus is the genetic variability that (United Nations Program on HIV / AIDS), in predominates especially in the env gene due 2019 the number of people with this infection to hypervariable regions and this represents was approximately 38 million, of which about a problem both to the existing treatment and 1.7 million were new cases, and 690.000 people to the implementation of a vaccine to prevent died of AIDS [11]. infection. CD4+ T helper lymphocytes have a The overall incidence peaked at 3.3 million central role in the host’s immune response to infected per year in 1997. It continued to HIV infection, by activating antibody-secreting decline to 2.6 million per year in 2005, and B lymphocytes (humoral-mediated response) then remained constant until 2015. At the last and cytotoxic lymphocytes (cell-mediated measurement in 2019, a decrease was observed, 196
Prevention of HIV infection through vaccination
reaching an incidence of 1.7 million [11]. The most affected area remains Africa, where
The most affected are the sexually active according to estimates in 2019 the following
people aged between 20 and 40, followed by data were recorded and are listed in the table
perinatal infections; in 20% of these cases, below (Table 1) [11].
children develop AIDS in the first year of life.
Table 1. Areas affected by HIV/AIDS
Number* of people infected
Affected geographical area Number* of AIDS deaths
with HIV
South and East Africa 20.7 million 470.000
Central and West Africa 6.5 million 330.000
Middle East and North Africa 240.000 8.000
Asia-Pacific 5.1 million 180.000
Central Asia and Eastern Europe 1.5 million 47.000
Central and Western Europe,
2.2 million 12.000
North America
Latin America 2.1 million 37.000
* = numbers represent an estimation
Approximately 90% of HIV-1 infections are • Subtype C: Sub-Saharan Africa, India,
M group viruses and are globally distributed as Brazil;
follows: • Subtype D: North Africa and the Middle
• Subtype A: Central and East Africa and East;
countries that were part of the Soviet Union; • Subtype F: Countries in South and
• Subtype B: Central and Western Europe, Southeast Asia;
North America, South America, Australia, • Subtype G: Central and West Africa;
North Africa, the Middle East and several • Subtypes H, J, and K: Africa and the
Asian countries, including Japan and Middle East [12].
Thailand;
Given that subtype B is dominant in Spain, and Belgium). From the P group only
economically developed countries (USA and one infection was discovered in a person from
Western Europe), most clinical trials have been France, originally from Cameroon [10].
conducted on it, although it is responsible for HIV-2 is found mainly in West African
only 12% of HIV infections globally. Subtype countries (Cape Verde, Ivory Coast, Gambia,
C is found in 50% of infections, but the fact that Guinea-Bissau, Mauritania, Mali, Niger,
it is dominant in poor countries, such as India Sierra Leone, Senegal, Liberia, Ghana, etc.).
and Africa, makes it less included in clinical There has been an increase in prevalence in
trials [10]. India and several cases have been reported in
N group viruses have been identified in Europe and the Americas, most often in people
several people from Cameroon. O group HIV- of West African descent. The greatest diversity
1 infections are found mainly in Central and of subtypes is found in Cameroon and D.R.
West Africa, and in small numbers in countries of the Congo. In the future, due to population
that used to have colonies in this area (France, migration, the distribution areas of various
197NICOLAE et al.
types of HIV will change [10, 13]. and Bictegravir;
1. Antiretroviral therapy • or Tenofovir alafenamide + Emtricitabine
and Raltegravir
The virus can be transmitted in several ways: • or Tenofovir disoproxil-fumarate +
sexually (heterosexually or homosexually) - Emtricitabine and Raltegravir.
70% according to the WHO, maternal-fetal 2 nucleoside reverse transcriptase
(prenatal, perinatal or postnatal), parenteral inhibitors and 1 non-nucleoside reverse
(in drug addicts), by blood transfusions or transcriptase inhibitor:
organ transplants or in occupational accidents. • Tenofovir alafenamide + Emtricitabine +
General prophylaxis measures refer primarily Ritonavir;
to protected sexual contact and the avoidance • or Tenofovir disoproxil-fumarate +
of sexual intercourse with people suspected of Emtricitabine + Ritonavir.
having the infection. But also to the prevention 2 nucleoside reverse transcriptase
of infection in young women, counselling and inhibitors and 1 protease inhibitor
antiretroviral treatment during pregnancy, potentiated by Ritonavir or Cobicistat:
choice of caesarean section and prohibition of • Tenofovir alafenamide + Emtricitabine
breastfeeding (these measures reduce the risk or Tenofovir disoproxil-fumarate +
of infection of the fetus to 0.3% according to Emtricitabine, in combination with Darunavir
the Romanian Anti-AIDS Association), careful + Cobicistat or Darunavir + Ritonavir [15-
selection of donors and wearing gloves and 16].
protective equipment [6, 14]. Despite the fact that there is antiretroviral
Antiretroviral therapy is established treatment that, properly instituted and
depending on the stage of HIV infection, monitored, has positive effects by increasing
physiological conditions (pregnancy), presence survival and delaying the onset of opportunistic
of immunodeficiency signs and the occurrence infections, it also has a number of limitations.
of opportunistic infections, patient’s age, and The most important is the lack of elimination
also on the tolerance to treatment. of the infection completely; the treatment only
Treatment aims to both reduce viral load reduces viral replication. Patients may also
and restore CD4+ and CD8+ T cell numbers, develop resistance to treatment over time [3].
along with decreasing viral replication in the
lymphatic and nervous systems and avoiding 2. Post-exposure prophylaxis of HIV
the development of resistance to treatment. In the absence of a protective immune
Currently, associated therapy is the standard, response or the existence of a vaccine that
and is called ART (“Anti-Retroviral Therapy”). can be administered after HIV infection, post-
The treatment regimen may have various HIV exposure prophylaxis is considered in
combinations of the following drug classes: emergencies and depending on the degree of
reverse transcriptase inhibitors, non-nucleoside risk. When it comes to low risk of infection, it is
reverse transcriptase inhibitors, protease not recommended to start antiretroviral therapy,
inhibitors or fusion inhibitors [15-16]. but it is considered in case of an intermediate
Antiviral therapy is started at the time of risk and is mandatory at high risk. The first
diagnosis, regardless of the number of CD4+ steps are risk assessment and rapid HIV and
cells, and the first intention is to use one of HCV testing. Prophylaxis in these situations is
these combinations: best to start in the first 4 hours after exposure
2 nucleoside reverse transcriptase and never exceed 48/72 hours after contact, and
inhibitors and 1 integrase inhibitor: antiretroviral therapy will be administered for 4
• Abacavir + Lamivudine and Dolutegravir; weeks, according to the following scheme:
• or Tenofovir alafenamide + Emtricitabine • Tenofovir disoproxil-fumarate +
and Dolutegravir Emtricitabine;
• or Tenofovir disoproxil-fumarate + • or Zidovudine + Lamivudine, to which
Emtricitabine and Dolutegravir; Raltegravir is added twice a day or Darunavir
• or Tenofovir alafenamide + Emtricitabine + Ritonavir once daily, or Lopinavir +
198Prevention of HIV infection through vaccination
Ritonavir twice daily; or HIV seroconversions are sought among
• or Tenofovir disoproxil-fumarate + participants [16].
Emtricitabine + Dolutegravir once daily The researchers explored a number of
[15-16]. strategies by which they hope to produce
VACCINE TYPES protective immune responses. These include:
• Vaccines consisting of recombinant
So far, more than 40 HIV vaccines have been subunits;
tested on several thousand volunteers. Most of • Vaccines with modified envelope;
this research consists of studies on the safety and • Vaccines with antigenic peptides;
efficacy of recombinant proteins, produced in a • Vaccines with HIV DNA;
variety of different ways. Despite encouraging • Vaccines with recombinant vectors;
evidence of human immune responses, it is • Vaccines against viral toxins [15].
unclear whether many of these vaccines could Most of the time, studies use a combination
prevent HIV infection [15]. of these vaccine types, in vaccines that contain
Vaccines are usually given to a large number a main (“prime”) structure and an adjuvant,
of people at high risk of infection. After a stimulant (“boost”) structure. Thus, two or more
certain period of time, the results of those who vaccines are combined to broaden or enhance
received the vaccine are compared with those immune responses [16].
of volunteers who received placebo and involve The table below (Table 2) presents the studies
the evaluation of antibodies in the blood or the currently underway or recently completed (last
response of CD8 T cells to HIV in the test tube, 5 years).
Table 2. Ongoing or recently completed studies
No. of
Starting Vaccine
Trial name Phase Concept Country Status
year type volunteers
DNA (the active component of the vaccine
that contains virus-derived genes) enters
CRO2049/ the cells that will use HIV genes to make
I 2014 DNA copies of viral proteins. These proteins 30 Great Britain Ongoing
CUT*HIVA-C000 should stimulate the immune system and
thus protect against infection. The vaccine
was administered SC, IM and ID [17]
To evaluate the safety and tolerability of
PENNVAX®-GP HIV-1 DNA vaccine and
DNA adjuvant IL-12, administered by ID
or IM injection with electroporation (EP)
in uninfected HIV adults. The injections
HVTN 098 I 2015 DNA 94 USA Completed
are performed with an EP device, which
uses an electrical impulse to open small
pores in the cells. Assesses whether EP
increases immune response to vaccine
[18]
Identification of optimal DNA delivery
DNA, conditions for amplifying the antibody
CUTHIVAC002 I 2015 24 Great Britain Ended
protein response to protein-modified intradermal
stimulation [19]
This study will evaluate the safety,
tolerability and immunogenicity of DNA- South Africa,
DNA,
HVTN 111 I 2016 HIV-PT123 (an HIV type C DNA vaccine) 132 Tanzania, Ongoing
protein
and Subtype B gp120 / MF59 in healthy, Zambia
HIV-uninfected adults [20]
To evaluate safety, tolerability and
immune response of the DNA-HIV-PT123
vaccine used in combination with one of
DNA, South Africa,
HVTN 108 I/II 2016 the 2 protein vaccines: bivalent subtype C 334 Completed
protein USA
gp120/MF59 (protein/MF59) or bivalent
subtype C gp120/AS01B (Protein/AS01B)
in HIV-uninfected adults [21]
199NICOLAE et al.
To evaluate safety, tolerability and
immunogenicity of two HIV-1 vaccines:
p24CE1/2 pDNA and p55^gag pDNA,
HVTN 119 I 2017 pDNA 56 USA Ongoing
with IL-12 pDNA adjuvant, in i.m.
administration with electroporation in
healthy, HIV-uninfected adults [15]
This study tests the mucosal-specific
immune response (HIV-specific IgA and
IgG in saliva, cervical secretions, semen,
DNA,
which may include neutralizing activity)
adeno-
HVTN 076 I 2011 obtained from the administration of a 45 USA Completed
virus
DNA-type HIV vaccine, followed by the
vector
administration of an HIV vaccine that
uses an adenoviral vector in seronegative
patients [22]
To evaluate the safety, tolerability, and
immunogenicity of four HIV vaccines
in HIV-uninfected adults. It includes
DNA,
three vaccines: Nat-B env DNA, CON-S
HVTN 106 I 2014 poxviral 105 USA Ongoing
enzyme DNA and env mosaic DNA, and
vector
a vaccine called MVA-CMDR that can
stimulate the immune response to DNA
vaccines [23]
To evaluate the safety and compare the
DNA, immunogenicity of the first DNA vaccine
USA,
HVTN 092 I 2013 poxviral plans, followed by a stimulation of the 209 Completed
Switzerland
vector NYVAC vaccine in healthy HIV-1-
uninfected adult participants [24]
DNA, To evaluate the safety and tolerability of
viral the HIV-1 nef/ tat/ vif vaccine, env pDNA
vector released by electroporation (EP), followed
HVTN 112 I 2016 15 USA Ongoing
by stimulation with the envC vaccine with
recombinant vesicular stomatitis virus
(rVSV), in HIV-uninfected adults [25]
To evaluate the safety, pharmacokinetics
Passive and the antiretroviral effects of anti-HIV-1
Germany,
10-1074 I 2015 immuni- strong neutralizing monoclonal antibody 33 Completed
USA
zation 10-1074 in HIV infected and non-infected
people [15]
Botswana,
To evaluate the safety and efficacy Kenya,
Passive of human monoclonal antibody mAb Malawi,
HVTN 703/HPTN
IIb 2016 immuni- VRC-HIVMAB060-00-AB (VRC01) in 1900 Mozambique, Ongoing
081 zation preventing HIV-1 infection in higher risk South Africa
exposed women [15] Tanzania
Zimbabwe
A randomized, placebo-controlled clinical
Passive study on the safety, pharmacokinetics
IAVI T001 I 2016 immuni- and antiviral activity of the monoclonal 63 USA Ongoing
zation antibody PGT121 (mAb) in HIV-
uninfected and HIV-infected adults [15]
To evaluate the safety and
Puerto Rico,
Passive pharmacokinetics of three monoclonal
South Africa,
IMPAACT P1112 I 2015 immuni- antibodies, VRC01, VRC01LS and 158 Completed
USA, Zim-
zation VRC07-523LS, in infants exposed to HIV
babwe
[15]
The first study of the monoclonal
antibody VRC-HIVMAB075-00-AB
(VRC07-523LS) in healthy adults. Dose
Passive
increase study to examine the safety,
VRC 605 I 2017 immuni- 26 USA Completed
tolerability, dose and pharmacokinetics
zation
of VRC07-523LS; verifies the safety of
administration to healthy adults by IV and
SC routes [15]
200Prevention of HIV infection through vaccination
To evaluate the efficacy of VRC01LS
and VRC07-523LS antibodies, as well
as the organism tolerance range. Part A
Passive of the research will study the VRCO1LS
VRC 607 I 2016 immuni- antibody, and part B VRC07-523LS. 20 USA Completed
zation Their blood concentration and dynamic
over time will be monitored, and also if
the patients develop an immune response
against these antibodies [15]
To evaluate the safety and efficacy of
Passive (VRC01) human monoclonal antibody in USA, Peru,
HVTN 704 AMP IIb 2016 immuni- preventing HIV-1 infection in men and 2700 Brazil, Ongoing
zation transgender persons who engage in sexual Switzerland
acts with men [15]
The first study of VRC-HIVMAB080-
00-AB (VRC01LS) (MAb) monoclonal
antibody in healthy adults. It is a dose
escalation study to evaluate the safety,
Passive tolerability, dose and pharmacokinetics of
VRC01LS I 2015 immuni- VRC01LS. 49 USA Completed
zation
The hypothesis is that VRC01LS is safe
to be administered IV and SC to healthy
adults [15]
To evaluate the safety, pharmacokinetics
and activity of 2 experimental
Passive
human monoclonal antibodies: VRC- South Africa,
HVTN 116 I 2017 immuni- 74 Ongoing
HIVMAB060-00-AB (VRC01) and USA
zation
VRC01LS in serum and mucosa in HIV
uninfected adults [15]
adeno-
To evaluate the safety, tolerability and
associa-
immunogenicity of the recombined vector
ted virus
coding AAV(rAAV1-PG9DP) for the
IAVI A003 I 2014 vector 21 Great Britain Completed
PG9 antibody when it is administered
contain-
intramuscularly, at different doses, to
ing gene
healthy male adults [15]
sequences
The main objective is to document the
safety of the gp120-CD4 full length
IHV01 I 2015 Protein single-chain (FLSC) complex vaccine, 65 USA Completed
with a secondary objective of assessing
induced immune responses [15]
To analyse in HIV-uninfected volunteers
the innate, cell-mediated and humoral
mediated responses induced by AIDSVAX
RV 328 II 2014 Protein B / E in the systemic and mucosal 40 Thailand Ongoing
compartments and to characterize the
functional specificities of B cells in
peripheral blood and bone marrow [15]
Randomized, double-blind clinical trial,
to evaluate the safety, immunogenicity of
Ad26.ENVA.01 Adeno-
mucous membranes and innate immune
Mucosal/ I 2010 virus 24 USA Completed
responses of the recombinant adenovirus
IPCAVD003 vector
HIV-1 vaccine serotype 26 (Ad26.
ENVA.01) in HIV-1 uninfected adults [15]
Randomized, double-blind, dose-
escalation study to evaluate the safety
Adeno-
Ad5HVR48. and immunogenicity of the recombinant
I 2009 virus 48 USA Completed
ENVA.01 serotype 5 HIV-1 HVR48 vaccine
vector
(Ad5HVR48.ENVA.01) in uninfected
HIV-1 adults [15]
To evaluate the safety and tolerability of
different vaccination regimes, Ad26.Mos
Adeno-
HIV and C Clade (gp) 140. The response
virus
IPCAVD010 I 2016 of envelope antibodies from different 36 USA Ongoing
vector,
vaccination schemes is also monitored.
protein
Monocentric, randomized, double-blind
[15]
Adeno-
Randomized, double-blind, multicenter
HVTN 118 virus Kenya,
II 2017 study. Participants are healthy adults, 155 Ongoing
IPCAVD-012 vector, Rwanda, USA
undiagnosed with HIV [15]
protein
201NICOLAE et al.
Follows the safety and tolerability of
different vaccine regimens containing Rwanda,
Viral
HIV (Ad26.Mos.HIV), modified Ankara South Africa,
IPCAVD009 I/II 2014 vector, 393 Completed
vaccine (MVA) and type 1 HIV-1 Clade C Thailand,
protein
serotype 26-mosaic vaccine (gp140 DP). Uganda, USA
Multicenter, double-blind [15]
Randomized, double-blind study to
examine the influence of antigenic
competition on the immunogenicity of
Adeno- Brazil, Peru,
HIV-1 Gag / Pol. Tests whether a vaccine
HVTN 084 I 2011 virus 100 Switzerland Completed
that includes only Gag and Pol peptides
vector USA
elicits a stronger immune response than
a vaccine that includes Env A, B, and C
peptides [15]
The strategy involves two vaccines, given
successively at different times in HIV-1
Adeno-
uninfected adults. The goal is to stimulate
HVTN 083 I 2010 virus 180 USA Completed
different parts of the immune system
vector
and enhance the body's overall immune
response to HIV [15]
The HIV VRC rAd5 vaccine contains
4 different components, gag-pol / env
Adeno- A / envB / envC. The researchers will
HVTN 085 Ib 2011 virus examine how the immune system 90 USA Ongoing
vector responds to the vaccine when the 4
components are administered in 3 different
ways to HIV-uninfected adults [15]
The purpose is to evaluate the safety,
Adeno- tolerability of the 2 different vaccination
HVTN 117
II 2016 virus regimens Ad26.Mos. HIV trivalent and 201 Rwanda, USA Ongoing
VAC89220HPX2004
vector Clade C gp140 or Ad26.Mos4 tetravalent
[15]
Adeno-
virus A study to assess the safety of candidates
PEACHI-04 I 2014 vector, with HIV and hepatitis C vaccines when 32 Great Britain Completed
Poxvirus given separately or in combination [15]
vector
The HIV Vaccine Testing Network
Poxviral (HVTN) conducted a study to test
HVTN 097 I 2013 vector, 2 experimental HIV vaccines in 100 South Africa Completed
protein combination with 2 licensed tetanus and
hepatitis B vaccines [15]
Double-blind clinical trial in HIV-
Poxvirus uninfected adults. Uses ALVAC-HIV
HVTN 100 I/II 2015 vector, (vCP2438) and bivalent gp120 / MF59. 252 South Africa Completed
protein These are experimental vaccines, used
only in research [15]
Randomized, double-blind clinical trial
Poxviral to evaluate the safety and efficacy of
HVTN 702 III 2016 vector, ALVAC-HIV (vCP2438) and the bivalent 5400 South Africa Completed
protein subtype Cgp120 / MF59 in the prevention
of HIV-1 infection in adults [15]
To evaluate the safety and tolerability of
delayed stimulation regimens of SIDAX
Poxviral
B / E monotherapy, ALVAC-HIV alone
RV 305 II 2012 vector, 162 Thailand Ongoing
or the ALVAC-HIV / AIDSVAX B / E
protein
combination in HIV-negative participants
[15]
The main purpose of the study is to
better define the relative contribution of
AIDSVAX® B / E alone, ALVAC-HIV
alone or ALVAC-HIV plus AIDSVAX®
B / E association to the immune profile
observed in the weeks and months after
Poxviral initial reception and the stimulation
RV 306 II 2013 vector, regimen of the vaccine from the study 360 Thailand Ongoing
protein protocol RV144 and their booster
effects in both systemic and mucosal
compartments. This study will provide
a more intense and comprehensive
characterization of innate, cell and
humoral-mediated immune responses than
in the RV144 study [15]
202Prevention of HIV infection through vaccination
To test experimental HIV vaccines that
use an adenovirus as a carrier. The vector
Replica-
can help vaccines stimulate an immune
tive viral
HVTN 110 I 2015 response. Researchers want to see the 60 USA Ongoing
vector,
post-vaccination immune response
protein.
and whether the vaccine adenovirus is
contagious [15]
To test experimental HIV vaccines
that use an adenovirus as a carrier.
Replica-
Researchers want to see if different ways
PXVX-HIV-100-001 I 2013 tive viral 61 USA Ongoing
of administering vaccines cause different
vector
immune responses. They also want to see
if adenovirus vaccines are contagious [15]
The study evaluates three subtype C
HIV vaccines. SAAVI DNA-C2 is a
vaccine composed of two DNA plasmids
in equal amounts, expressing a subtype
Poxviral C HIV-1 polyprotein, comprising Gag-
HVTN 086, SAAVI vector, Tat-Nef transcriptase and Env peptides.
I 2011 185 South Africa Completed
103 DNA, SAAVI MVA-C is a live, modified
protein Vaccinia Ankara virus vaccine that
contains the same antigens as SAAVI
DNA-C2. Novartis Subtype C gp140 is
a glycoprotein vaccine 140 administered
with MF59 adjuvant [15]
Particles Bivalent DNA-protein anti-HIV1 vaccine
CombiHIVvac
II 2019 resem- containing multiple HIV1 protein epitopes 30 Russia Ongoing
(KombiVI Chvak) bling virus of T and B cells [15]
To evaluate the response to 2 different
vaccination schemes with an HIV DNA
vaccine (HIV-DNA-PT123) or HIV with
NYVAC (PT1 and PT4) vaccine followed
by a combined stimulation with HIV
DNA, USA, South
HVTN 101 I 2019 NYVAC (PT1 and PT4) and AIDSVAX 264 Ongoing
protein Africa
B / E. It will also assess whether BMI
and / or gender influence immunogenicity
and analyse regional differences in
immunological responses between
participants in the 2 countries [15]
To follow the response to AIDSVAX B /
E and MVA / HIV62B in HIV-uninfected
Protein,
HVTN 114; individuals who have previously received
I 2019 poxviral 100 USA Ongoing
GOVX-B11 MVA / HIV62B in DNA / MVA or MVA
vector
/ MVA vaccine regimens as part of the
HVTN study 205 [15]
The volunteers with low-risk HIV
infection from RISVAC02 study were
Poxviral
RisVac02boost I 2019 randomly assigned to get 3 MVA-B 24 Spain Ongoing
vector
IM shots. They will receive another
stimulating dose [15]
It can be hypothesized that HIVIS DNA
and MVA-CMDR vaccination will lead
DNA, to a reduction in HIV reservoir markers
RV534 I 2020 viral as a result of vaccine-induced immune 45 Brasil, Peru Ongoing
vector responses. The effects may be superior
with the addition of TLR4 agonist as
immune adjuvant [15]
To Evaluate the Safety and
Immunogenicity of Recombinant HIV-1
USA,
IAVI C101 I 2020 Proteic Envelope Protein BG505 SOSIP.GT1.1 48 Ongoing
Netherlands
gp140 Vaccine, Adjuvanted in Healthy,
HIV-uninfected Adults [15]
Vaccines with recombinant viral vectors
AIDSVAX B/E vaccine performed on 16,000 participants in Thailand
The RV144 trial, also called the “Thailand over a period of 6 years. Two experimental
Study”, had a significant impact on the field vaccines were used; the first one was a
of HIV vaccination, with the study being recombinant type vaccine, using a virus from
the Avipoxvirus family, with inserted genes
203NICOLAE et al.
encoding HIV antigenic proteins, intended of the HIV vaccine used in this study and the
to stimulate cell-mediated immunity through existence of a common immune response to
T cells, and the second one an experimental authorized vaccines for tetanus and hepatitis B.
stimulant vaccine, containing an antigenic HVTN is an interventional, randomized
surface protein produced by HIV, aiming to study involving 100 volunteers aged between
stimulate the production of antibodies. The two 18 and 40 years, starting in 2013 in South
types of vaccines, used together, had a moderate Africa. The participants included in the study
effect on the prevention of HIV infection, had no previous pathologies, being clinically
with an immunization rate of 31%. This result and imagistically healthy, willing to receive
contributes to the hope of researchers to make vaccines against tetanus and hepatitis B,
possible an effective anti-HIV vaccine [15, 26]. evaluated with low risk for HIV infection.
Starting from this trial, attempts are being The following were used for treatment:
made to obtain additional vaccines that could - ALVAC HIV (lyophilized vaccine,
enhance protective immune correlations. intramuscular injection, reconstituted from 1.05
The reduction in the risk of HIV infection ml of sterile 0.4% NaCl solution for a single
is largely correlated with the total binding of dose of 1 ml > 1.0x 106 CCID50 / ml);
plasma IgG to the gp70 of the leukemic virus - AIDSVAX B / E (HIV glycoprotein gp120
in mice, containing HIV-1 gp120 with variable subtype B 300 mcg and glycoprotein gp120
regions 1 and 2 (gp70 V1-V2). A similar subtype E 300 mcg absorbed on 600 mcg of
correlation was observed with total plasma aluminium hydroxide adjuvant gel);
IgG binding to V2 linear peptides and IgG 3 - hepatitis vaccine (each 1 ml dose contains
binding to V1-V2 gp70 schemes. These V1-V2 20 mcg of hepatitis B surface antigen (HBsAg)
antibodies appear to bind the middle region of adsorbed on 500 mcg of aluminium as
V2 by a strong dependence on lysine at position aluminium hydroxide, for IM administration);
169 and valine at position 172. Consistent - tetanus vaccine (tetanus toxin absorbed
with these findings, two genetic analyses of on aluminium hydroxide dihydrate, IM
viruses discovered in the RV144 trial identified administration) [28].
increased efficacy against lysine (K)-containing RV 305/306 studies - bivalent vaccine
viruses at position 169. Because CD8+ virus testing
neutralizing antibodies and level 2 virus The purpose of this study is to evaluate the
neutralizing antibodies were almost absent in safety and tolerability of regimens with delayed
this test, a hypothesis was raised that protection stimulation of AIDSVAX B / E alone, ALVAC-
was mediated by non-neutralizing antibodies. HIV alone or the ALVAC-HIV / AIDSVAX B
In this regard, the results of several RV144 / E combination in uninfected HIV participants
follow-up studies implicate a role of the effector in RV144.
functions of Fc receptor-mediated (FcR) non- The study is interventional, randomized,
neutralizing antibodies, including Antibody- double-blind, in which 162 adult volunteers
Dependent Cellular Cytotoxicity (ADCC) and participated, starting in April 2012, Thailand.
phagocytosis [27]. Subjects included in the study participated in
ALVAC HIV vaccine the RV144 trial, received the active product and
performed the 4 protocol vaccination visits.
The HIV Vaccine Trial (HVTN 097) is a The volunteers were organized in 3 groups:
study that aims to test two experimental HIV • The first group was tested with ALVAC
vaccines, used in conjunction with two licensed HIV 1 ml per injection containing 10X6
vaccines for tetanus and hepatitis B. CCID50 administered dose, AIDSVAX B /
This study seeks answers regarding effective E 1 ml per injection, ALVAC-HIV placebo
and safe vaccination in the uninfected 1 ml, AIDSVAX B / E APLACEBO 1 ml,
population, how the immune system responds weeks 0-24;
to the action of HIV vaccine, if the immune • The second group was tested with
response to tetanus and hepatitis B vaccination AIDSVAX B / E 1 ml and placebo 1 ml,
can help understand the mechanism of action weeks 0-24;
204Prevention of HIV infection through vaccination
• The third group was tested with ALVAC- Despite many failed attempts to induce
HIV 1 ml and placebo 1 ml, weeks 0-24 protective immunity, researchers are
(29). increasingly optimistic that scientific progress
Neutralizing antibody vaccines will eventually lead to success. While the path
to the development of effective vaccines and
The International AIDS Vaccine Initiative antibodies against HIV may still be a long one,
(IAVI) is a non-profit scientific organization it is at least clearer [22, 30–32].
established in 1996 that aims to develop
vaccines and other biomedical innovations DNA-based vaccines
that prevent HIV infection. IAVI is committed The study on DNA-based HIV vaccination
to supporting the broad field of HIV vaccine took shape 20 years ago. Significant experience
research. has been gained in vector design, antigen
In 2009, the first antibody capable of optimization, use of DNA immunization,
neutralizing the HIV virus was isolated, being as part of the vaccination strategy. With a
isolated from HIV-infected volunteers. It has better understanding of the potential for DNA
been found that antibodies bind to proteins, immunization and recent advances in HIV
making it difficult for them to get past the vaccine research, it is anticipated that DNA
carbohydrate “shield.” Some patients develop immunization will play a more important role
the so-called neutralizing antibodies (bNAbs). in HIV vaccine development.
It has been shown that some broadly An ongoing study, started in 2015 in
Neutralizing Antibodies (bNAbs) can provide the USA, aims to evaluate the safety and
protection against HIV or a hybrid virus known immunogenicity of the PENNVAX®-GP
as SHIV. This protection is largely due to their DNA vaccine and the DNA adjuvant, IL-12,
ability to effectively neutralize the virus. administered intradermally or intramuscularly
An antibody that appears to neutralize almost by electroporation in HIV-uninfected adults.
all viruses is 10E8. This antibody targets Researchers will also look at whether
the proximal outer region gp41 of the virus electroporation promotes an improved immune
membrane. Unfortunately, its usefulness in response to the vaccine.
prophylaxis is questioned. Adverse reactions The study involves 94 volunteers, who
such as erythema or redness at injection were divided into four groups. In each group,
sites have been reported in seven of the eight participants were given either the PENNVAX®-
individuals who received this antibody, but no GP DNA / IL-12 vaccine or a placebo serum.
severe side effects. Each group received different doses of the
A tri-specific antibody designed by scientists vaccine. Enrolment began with group 1, which
from Sanofi and VRC that combines the antigen received a low dose of vaccine and adjuvant.
binding fragment (Fragment antigen binding - Researchers examined group 1 safety data
Fab) of three bNAbs molecules, including 10E8, before administering higher doses to groups 2,
into a single molecule is currently being studied. 3 and 4 [18, 33]
The researchers say that the safety issues of the Another ongoing study was launched in May
10E8 antibody are diminished by using only a 2016 in southern Africa. This study evaluates
part of it, not the whole antibody. the safety, tolerability and immunogenicity of
Work is also underway to obtain stronger the HIV class C DNA vaccine and of the gp120
neutralizing antibodies with a longer half-life, / MF59 subtype B vaccine in healthy, HIV-
as well as to obtain antibody combinations that negative adults, aged 18 to 40 years.
would be more likely to protect against HIV. Participants were divided into six groups.
Longer-acting antibodies 3BNC117-LS and 10- Each group received the experimental vaccine
1074-LS, developed by Rockefeller University (DNA-HIV-PT123) and proteins (Protein /
scientists, are already being tested alone and MF59 vaccine) or placebo [21].
in combination in a phase I study involving New research directions
both HIV-infected volunteers and uninfected
volunteers. There are multiple challenges regarding
the development of an effective HIV vaccine:
205NICOLAE et al.
the virus quasi-species biology, the complex shots. All things considered, this subject
interactions between the virus and the immune remains vastly unexplored, filled with research
system, the incomplete understanding of all the opportunities.
immune mechanisms of the human body. Conflict of interests: The authors declare no
When it comes to the development of an conflict of interest.
effective HIV vaccine, the medical research
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