• Users Online: 556
  • Home
  • Print this page
  • Email this page
Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 


 
 Table of Contents  
REVIEW ARTICLE
Year : 2018  |  Volume : 3  |  Issue : 5  |  Page : 20-24

An update on newer vaccines in development phase for malaria, tuberculosis, and human immunodeficiency virus/acquired immune deficiency syndrome


Department of Community Medicine, School of Public Health, PGIMER, Chandigarh, India

Date of Web Publication11-Dec-2018

Correspondence Address:
Dr. Madhu Gupta
Department of Community Medicine, School of Public Health, PGIMER, Chandigarh - 160 012
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jncd.jncd_10_18

Rights and Permissions
  Abstract 


Malaria, tuberculosis (TB), and human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) are the three major public health problems globally and especially affecting many in low-income countries, particularly in Sub-Saharan Africa and Southeast Asian region. For many years, these three most devastating diseases have received most of the world's attention. The effective public health interventions in managing and controlling these diseases are able to reduce the burden to some extent but are not able to effectively prevent the occurrence of these diseases. Hence, lot of research is simultaneously going on in developing safe and effective vaccines against these diseases. Despite the continuous efforts to produce the effective vaccines against these diseases, there has not been much success, except recently for malaria, where anti-sporozoite subunit vaccine, RTS, S/AS01, has completed Phase III vaccine trials and got the positive regulatory assessment from the WHO. This review updates on the newer vaccines in the development phase for malaria, TB, and HIV/AIDS.

Keywords: Acquired immune deficiency syndrome, human immunodeficiency virus, malaria, tuberculosis, vaccine


How to cite this article:
Gupta M, Kaushal K. An update on newer vaccines in development phase for malaria, tuberculosis, and human immunodeficiency virus/acquired immune deficiency syndrome. Int J Non-Commun Dis 2018;3, Suppl S1:20-4

How to cite this URL:
Gupta M, Kaushal K. An update on newer vaccines in development phase for malaria, tuberculosis, and human immunodeficiency virus/acquired immune deficiency syndrome. Int J Non-Commun Dis [serial online] 2018 [cited 2022 Jan 18];3, Suppl S1:20-4. Available from: https://www.ijncd.org/text.asp?2018/3/5/20/247253




  Introduction Top


Malaria, tuberculosis (TB), and infection with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) collectively cause more than five million deaths per year but have nonetheless eluded conventional vaccine development; for this reason, they represent one of the major global public health challenges, as we reach toward the end of the 2nd decade of the 21st century.[1] Recent vaccine trials have provided evidence that it is possible to develop vaccines that can prevent infection by HIV and malaria and modify the response to existing TB vaccines. Advances in vaccinology, including novel adjuvants, prime-boost regimens, and strategies for intracellular antigen presentation, have led to progress in developing a vaccine against TB. In this review, we have summarized the vaccine research done so far and updated on the status of the newer vaccines in the developmental phase for these diseases.


  Malaria Vaccine Top


Malaria is the most devastating parasitic disease afflicting humankind. About 43,800 people died due to malaria in 2015, and most of these deaths were reported from Sub-Saharan Africa and Southeast Asia and South America.[2] The disease results from infection with protozoan parasites of the genus, Plasmodium, and is transmitted by female Anopheles mosquitoes. A long-lasting, broadly efficacious malaria vaccine would be the most sustainable approach to control and eventually eradicate malaria. A malaria vaccine that may be feasible is strongly supported by the fact that people living in malaria-endemic areas develop protective immunity against malaria symptoms during childhood. There are more than thirty Plasmodium falciparum malarial vaccine candidates, which are being evaluated worldwide in different stages of clinical trials, including two indigenous vaccines from India.[3],[4] These are presented in [Table 1].
Table 1: Malaria candidate vaccines being evaluated worldwide

Click here to view


After more than 50 years of intensive research and development, only one malaria vaccine candidate, i.e., anti-sporozoite subunit vaccine, RTS, S/AS01, has completed the Phase III evaluation and got the positive WHO regulatory assessment.[5] Despite only partial efficacy, this candidate is now forecasted to become the first licensed malaria vaccine. This vaccine is based on the recombinant virus-like particles of hepatitis B surface antigen displaying repeats from the P. falciparum circumsporozoite protein. It is preerythrocytic-stage hybrid recombinant protein vaccine. Results of a large multicenter Phase III trial of RTS, S/AS01, involving more than 15,000 children over 11 sites in Sub-Saharan Africa, have shown vaccine efficacy (VE) against clinical malaria of 51.3% (severe disease of 44.5%) after 12 months, 45.7% (severe disease of 37.7%) after 18 months, and 26% (severe disease of 2.2%) for whole period of 48 months after administering three doses in children aged 5–17 months at 1st vaccination and of 27% (severe disease of 15%) in infants aged 6–12 weeks at 1st vaccination.[6] VE after administering four doses was 39% against clinical malaria and 31.5% against severe malaria for the whole period (48 months). The RTS, S/AS01 Clinical Trials Partnership reported the safety and VE of the RTS, S/AS01 vaccine during 18 months following vaccination at 11 African sites with varying malaria transmission.[7] Despite this positive outlook, it is cautioned that this vaccine is only partially protective against disease and wanes over time. The WHO recommends pilot implementation of this vaccine with four dosage schedules in 3–5 distinct epidemiological settings, to examine the extent to which this vaccine impacts all-cause mortality including gender-specific mortality, and excess cases of meningitis and cerebral malaria need to be investigated for their causal association.[5]


  Tuberculosis Vaccine Top


TB is the ninth leading cause of death worldwide and the leading cause from a single infectious agent, ranking above HIV/AIDS. In 2016, there were an estimated 1.3 million TB deaths among HIV-negative people (down from 1.7 million in 2000) and an additional 374,000 deaths among HIV-positive people.[8] The only licensed vaccine against TB, Bacillus Calmette–Guérin (BCG), protects against severe extrapulmonary forms of TB but is virtually ineffective against the most prevalent form of the disease, i.e., pulmonary TB. Currently, about 16 types of TB vaccines are being tested in different phases as shown in [Table 2].[9] The aim of the development of new TB vaccine is the generation of long-lasting protection against the most prevalent form of pulmonary TB in all age groups and focus on either replacement of BCG or as a booster following vaccination with prime BCG. A double-blind, randomized, placebo-controlled trial is considered the optimum design for a Phase III efficacy trial. For a disease where no current vaccine is available (such as for HIV or malaria), the ethics of trial design is focused on appropriate sample size and selection of placebo. The rabies vaccine is considered a good placebo for malaria as this will offer some benefit to those participants not receiving the malaria vaccine. For a new TB vaccine, the scenario is different due to the currently available TB vaccine, BCG. BCG is one of the most widely administered vaccines in the world and despite varying efficacy does provide some protection against childhood forms of TB. To date, it has been the view of researchers, ethics committees, and regulatory agencies that in a country where TB is endemic, it would be unethical to withhold the BCG vaccine in a randomized control trial of a new TB vaccine. This view has driven the development of vaccines designed to work in combination with BCG and slowed the development of vaccines designed to replace BCG. For a vaccine designed to enhance previous BCG vaccination, a randomized placebo-controlled trial of the boosting vaccine is possible without withdrawing BCG vaccination.[10]
Table 2: Tuberculosis vaccines being tested in different phases

Click here to view


The new TB vaccine (VPM1002) is a recombinant BCG vaccine. VPM1002 is a formulated, lyophilized cake of live recombinant Mycobacterium bovis rBCG. VPM1002 is the active pharmaceutical ingredient. It is a genetically modified BCG vaccine derived from the M. bovis BCG subtype. The available preclinical and clinical data reveal that VPM1002 is immunogenic and may be better than BCG in terms of safety. VPM1002 could be a safe, well-tolerated, and efficacious alternative to the BCG vaccine in the future. With an annual capacity of 100 million doses, Serum Institute of India Private Limited can meet the global demand for a BCG vaccine and is well poised to supply the new vaccine if efficacy trials are successful.[11] Serum Institute of India Private Limited is conducting Phase II/III trial with two groups of adults successfully cured of Category 1 pulmonary TB receiving either VPM1002 or placebo. Single dose of VPM1002/placebo will be administered to calculate efficacy of the vaccine against TB recurrence. This study is designed as a multicenter, double-blinded, randomized, placebo-controlled trial with two groups of Category 1 pulmonary TB patients who have successfully completed anti-TB treatment and declared cured by bacteriological confirmation in India.[12]


  Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome Top


More than 40 million adults and children are living with HIV/AIDS worldwide and close to 5 million people (including 800,000 children) become infected each year.[13] HIV/AIDS is the leading cause of death in Sub-Saharan Africa and the fourth biggest killer worldwide. Asia currently experiences the world's fastest growing HIV/AIDS epidemic. Highly active antiretroviral therapy has reduced progression to AIDS, deaths, and HIV transmission from mother to child in North America and Western Europe. However, success with treatment has not been matched by progress toward prevention, and evidence of rising HIV infection rates is emerging, particularly in marginalized communities.

Development of a safe, effective, and affordable HIV vaccine remains the scientific and public health challenge of this new century. It is hampered by the tremendous genetic variability of the virus and the paucity of knowledge on possible immune mechanisms of protection. The first clinical trial of an HIV vaccine was conducted in the United States in 1987. Since then, over 30 candidate vaccines have been tested in over 80 Phase I/II clinical trials, involving over 10,000 healthy volunteers.[14] Most of these trials have been conducted in the United States and Europe. A few trials also have been conducted in developing countries (Brazil, China, Cuba, Haiti, Kenya, Thailand, Trinidad, and Uganda) as well. The effort to develop and evaluate HIV vaccines was strengthened by the African AIDS Vaccine Programme.[15]

Traditional approaches of using live-attenuated or whole-inactivated viruses were considered unsafe for the development of HIV vaccines because of the risk of permanently integrating proviral DNA within host chromosomes. Advancements in vaccine development had to wait until the mid-1980s when recombinant DNA technologies were becoming available. There are three scientific paradigms that have attracted researchers including induction of neutralizing antibodies, induction of CD8 T-cell-mediated immunity, and combination approaches. The status of HIV vaccines under development under these three approaches is presented in [Table 3].[16]
Table 3: Human immunodeficiency virus vaccines under development

Click here to view


Two gp120 products emerged as potential candidates for an efficacy trial under induction of neutralizing antibodies approach including VAX003 and VAX004. The Phase III VaxGen AIDSVAX gp120 trial failed to produce protection among men having sex with men in North America and drug users in Thailand, and it showed no VE.[17],[18] Disappointing results of VaxGen trial made HIV researchers to turn from B-cell-targeted vaccines designed to induce neutralizing antibodies to T-cell targeted approach.[19] In 1998, it was observed that live attenuated canarypox virus expressing HIV antigens were capable of inducing CD8 cytotoxic T-cells against Env- or Gag-expressing target cells in 64% of the volunteers. This study established the prime-boost concept for future HIV vaccine research. The cytotoxic T-lymphocyte vaccine approach was to develop a vaccine designed to lower viral set point and delay disease progression, rather than to prevent initial infection. Hence, STEP and Phambili HIV vaccine was tested in trials.[20] However, the results were not encouraging. Then, vaccines based on combination approaches were developed and tested. RV144 trial turned out to be the first trial of a vaccine against HIV-1 to show any degree of efficiency. RV144 was a randomized, multicenter, double-blind, placebo-controlled efficacy trial of recombinant canarypox vector vaccine done among 16,402 health participants in Thailand.[21] The 1st-year VE approached 60%; however, the efficacy waned over time to 31.2% (95% confidence interval, 1.1–52.1; P = 0.04) over 42 months suggesting early but nondurable vaccine effect.

Recently, Kang and Gao review on strategies employed for the development of HIV vaccines emphasized on the killed whole-virus vaccine approach.[22] SAV001-H was the first preventive HIV vaccine which was developed using a killed or “dead version” of HIV-1 virus by Kang et al., at Western University's Schulich School of Medicine and Dentistry in Canada. The result of the US, FDA, Phase I clinical trial, which was completed in 2013, showed no serious adverse effects in 33 participants. Vaccination with SAV001, the genetically modified and killed whole-HIV-1 vaccine, could enhance humoral immune responses including broadly neutralizing antibody production in HIV-negative individuals.[23] Therefore, SAV001 represents a promising starting point for the development of a safe and effective prophylactic HIV-1 vaccine using the killed whole-virus approach. This approach could be easily adaptable to include different subtypes of HIV-1.


  Conclusions Top


It is stated that malaria vaccine, RTS, S/AS01, has completed Phase III trial and obtained the WHO-positive regulatory assessment. However, the WHO does not recommend its use in younger age category as VE is low and recommends to further examine its impact on all-cause and gender-specific mortality and its efficacy in different epidemiological settings. For TB, there are about 16 candidate vaccines in different phases of development and their results are awaited. One of the candidate vaccines for TB is being tested in India as well (VPM1002). For HIV/AIDS, SAV001 represents a promising starting point for the development of a safe and effective prophylactic HIV-1 vaccine using the killed whole-virus approach. The quest to develop a successful HIV, TB, and malaria vaccine is long and winding. We are entering the modern era of HIV, malaria, and TB vaccinology due to a better understanding of the immune mechanisms and pathways and newer forms of vaccine immunogens. Hopefully, we will have better malaria, TB, and HIV vaccines in the future.

Acknowledgment

We thank the organizers of the World NCD Congress, 2017, held in PGIMER, Chandigarh, for giving us this opportunity to write this article.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Vitoria M, Granich R, Gilks CF, Gunneberg C, Hosseini M, Were W, et al. The global fight against HIV/AIDS, tuberculosis, and malaria: Current status and future perspectives. Am J Clin Pathol 2009;131:844-8.  Back to cited text no. 1
    
2.
World Health Organization. World Malaria Report 2015. Geneva, Switzerland: World Health Organization; 2015. Available from: http://www.apps.who.int/iris/bitstream/10665/200018/1/9789241565158_eng.pdf. [Last accessed on 2016 Jan 28].  Back to cited text no. 2
    
3.
World Health Organization. Tables of Malaria Vaccine Projects Globally “The Rain-Bow Tables; 2015. Available from: http://www.who.int/immunization/research/development/Rainbow_tables/en/. [Last accessed on 2018 Jan 28].  Back to cited text no. 3
    
4.
Malaria Vaccines Development Efforts in India Through DBT Support. Departmemt of Biotechnology. Ministry of Science and Technology. Available from: http://www.dbtindia.nic.in/malaria-vaccines-dev-efforts-dbt/. [Last accessed on 2018 Feb 17].  Back to cited text no. 4
    
5.
Malaria vaccine: WHO position paper-January 2016. Wkly Epidemiol Rec 2016;91:33-51.  Back to cited text no. 5
    
6.
Otieno L. Efficacy of RTS, S/AS01 Vaccine Candidate Against Malaria in African Infants and Children 8 Months Post-Primary Vaccination Series: A Phase III Randomized, Double-Blind Controlled Trial. Multilateral Initiative on Malaria Pan Africa Conference Durban; 2013.  Back to cited text no. 6
    
7.
RTS, S Clinical Trials Partnership. Efficacy and safety of the RTS, S/AS01 malaria vaccine during 18 months after vaccination: A phase 3 randomized, controlled trial in children and young infants at 11 African sites. PLoS Med 2014;11:e1001685.  Back to cited text no. 7
    
8.
WHO. Global TB Report 2017. Available from: http://www.apps.who.int/iris/bitstream/10665/259366/1/9789241565516-eng.pdf?ua=1. [Last accessed on 2018 Feb 16].  Back to cited text no. 8
    
9.
Usman MM, Ismail S, Teoh TC. Vaccine research and development: Tuberculosis as a global health threat. Cent Eur J Immunol 2017;42:196-204.  Back to cited text no. 9
    
10.
Fletcher HA, Hawkridge T, McShane H. A new vaccine for tuberculosis: The challenges of development and deployment. J Bioeth Inq 2009;6:219-28.  Back to cited text no. 10
    
11.
Nieuwenhuizen NE, Kulkarni PS, Shaligram U, Cotton MF, Rentsch CA, Eisele B, et al. The recombinant bacille calmette-guérin vaccine VPM1002: Ready for clinical efficacy testing. Front Immunol 2017;8:1147.  Back to cited text no. 11
    
12.
Study to Check the Efficacy and Safety of Recombinant BCG Vaccine in Prevention of TB Recurrence in India. Available from: https://www.clinicaltrials.gov/ct2/show/NCT03152903. [Last accessed on 2018 Jan 19].  Back to cited text no. 12
    
13.
HIV/AIDS. Fact Sheet. Available from: http://www.who.int/mediacentre/factsheets/fs360/en/. [Last accessed on 2018 Jan 19].  Back to cited text no. 13
    
14.
Esparza J. An HIV vaccine: How and when? Bull World Health Organ 2001;79:1133-7.  Back to cited text no. 14
    
15.
Klausner RD, Fauci AS, Corey L, Nabel GJ, Gayle H, Berkley S, et al. Medicine. The need for a global HIV vaccine enterprise. Science 2003;300:2036-9.  Back to cited text no. 15
    
16.
Shin SY. Recent update in HIV vaccine development. Clin Exp Vaccine Res 2016;5:6-11.  Back to cited text no. 16
    
17.
Pitisuttithum P, Gilbert P, Gurwith M, Heyward W, Martin M, van Griensven F, et al. Randomized, double-blind, placebo-controlled efficacy trial of a bivalent recombinant glycoprotein 120 HIV-1 vaccine among injection drug users in Bangkok, Thailand. J Infect Dis 2006;194:1661-71.  Back to cited text no. 17
    
18.
Flynn NM, Forthal DN, Harro CD, Judson FN, Mayer KH, Para MF, et al. Placebo-controlled phase 3 trial of a recombinant glycoprotein 120 vaccine to prevent HIV-1 infection. J Infect Dis 2005;191:654-65.  Back to cited text no. 18
    
19.
Fauci AS, Marston HD. Public health. Toward an HIV vaccine: A scientific journey. Science 2015;349:386-7.  Back to cited text no. 19
    
20.
Buchbinder SP, Mehrotra DV, Duerr A, Fitzgerald DW, Mogg R, Li D, et al. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the step study): A double-blind, randomised, placebo-controlled, test-of-concept trial. Lancet 2008;372:1881-93.  Back to cited text no. 20
    
21.
Karasavvas N, Billings E, Rao M, Williams C, Zolla-Pazner S, Bailer RT, et al. The Thai phase III HIV type 1 vaccine trial (RV144) regimen induces antibodies that target conserved regions within the V2 loop of gp120. AIDS Res Hum Retroviruses 2012;28:1444-57.  Back to cited text no. 21
    
22.
Kang CY, Gao Y. Killed whole-HIV vaccine; employing a well established strategy for antiviral vaccines. AIDS Res Ther 2017;14:47.  Back to cited text no. 22
    
23.
Choi E, Michalski CJ, Choo SH, Kim GN, Banasikowska E, Lee S, et al. First phase I human clinical trial of a killed whole-HIV-1 vaccine: Demonstration of its safety and enhancement of anti-HIV antibody responses. Retrovirology 2016;13:82.  Back to cited text no. 23
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
   Abstract
  Introduction
  Malaria Vaccine
  Tuberculosis Vaccine
   Human Immunodefi...
  Conclusions
   References
   Article Tables

 Article Access Statistics
    Viewed2143    
    Printed155    
    Emailed0    
    PDF Downloaded59    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]