The Search for an HIV Vaccine Continues

HIV Vaccine Awareness Day, also known as World AIDS Vaccine Day, is celebrated each year on May 18.¹ Four decades into the HIV/AIDS pandemic, the holy grail of a vaccine against the deadly virus remains an elusive achievement, marked by both advancements and setbacks.

“I’ve been asked dozens of times, ‘Oh, you think if everybody was affected by HIV in the 80s, we’d have a vaccine right now?’, and I’m like, ‘Maybe, maybe,’” said Perry N. Halkitis, PhD, MS, MPH, dean of the Rutgers School of Public Health and director of the Center for Health, Identity, Behavior and Prevention Studies, in an interview with The American Journal of Managed Care^® (AJMC^®). “In the next 10 or 15 years, likely we’ll have a vaccine.”

“As with COVID-19, the problem with HIV is this thing mutates constantly,” he continued. “So that’s a challenge we have with COVID-19 that we have with HIV also: There’s just so many subtypes out there.”

Halkitis hits on a sentiment echoed by many in the almost 4 decades since the pandemic began: An effective vaccine against HIV and AIDS has not been successfully produced. Many have tried, but only the RV-144 Prime-Boost HIV Vaccine trial has seen positive results, and only then regarding reduction in the HIV infection rate.²

This trial, which took place in Thailand, investigated 2 vaccine-related outcomes: prevention of HIV infection and reduction of HIV viral load in trial participants who contracted the virus after enrollment.²

According to the National Institute of Allergy and Infectious Diseases (NIAID), “The development of a safe and effective HIV vaccine remains key to realizing a durable end to the HIV pandemic.”³

Of the 5 most well-known HIV vaccine trials, of which RV-144 is one, 3 have seen their vaccine candidates fail and 2 are ongoing:

• HVTN 702 was initiated in 2016 in South Africa. Results were expected by the end of this year,⁴ but the trial was stopped in February 2020 because the vaccine candidate was deemed ineffective. Despite none of the 5400 participants having HIV when the trial began, 4.5% were living with HIV when the study was stopped.⁵
• RV-144 began in September 2003² and findings were published in the New England Journal of Medicine in 2009.⁶ The 31.2% efficacy vs placebo was deemed modest, but there was no change in viral load among study participants given the investigational drug or placebo who acquired HIV over the course of the study.²
• STEP began in December 2004 but was halted and unblinded in 2007 for safety concerns; its investigative vaccine candidate failed to show efficacy at preventing HIV-1 acquisition or reducing plasma HIV-1 RNA levels. In addition, a possibly higher risk of infection with HIV was seen in those who received the vaccine candidate.⁷
• Imbokodo⁸ is ongoing among heterosexual women in 5 countries of sub-Saharan Africa: South Africa, Zimbabwe, Mozambique, Malawi, and Zambia. Also known as HVTN 705,⁹ “mosaic immunogens are being investigated for their potential to induce immune responses against a wide variety of global HIV strains,” according to the National Institutes of Health.⁴ The expected completion date is July 23, 2022.⁸
• Mosaico, or HVTN 706,¹⁰ also is investigating mosaic immunogens, but this study population consists of gay men and transgender women from the United States, Latin America, and Europe.⁴ The expected completion date is March 13, 2024.¹¹

For Imbokodo and Mosaico, 6 intramuscular injections each are administered over a 12-month period, with 1 injection each at months 0 and 3 and 2 injections each at months 6 and 12.^8,11

“The presumption is that a mosaic is going to give you broader coverage,” Anthony S. Fauci, MD, director of NIAID, has said.⁴

The search for a vaccine against HIV and AIDS began almost immediately after the first CDC Morbidity and Mortality Weekly Report (MMWR) was published in 1981 detailing observations of a cluster of 5 cases of Pneumocystis carinii pneumonia (PCP) among gay men in Los Angeles.¹² PCP is typically confined to patients with severely compromised immune systems—such as those with cancer or autoimmune/inflammatory diseases and individuals who have undergone organ or stem cell transplants—but 4 of the 5 men (one had a history of Hodgkin disease) had no such experience with immunocompromised status.^12,13

It took 2 years¹⁴ before virologists from the Pasteur Institute in France and the National Cancer Institute in the United States separately identified lymphadenopathy-associated virus and human T-cell lymphocyte virus type III, respectively, which turned out to be the same virus¹⁵—and the reason for the sudden illness in the 5 men from the CDC report.¹²

Their findings confirmed the suspicions outlined by Michael Gottlieb, MD, lead author on that first CDC report,^12,14 and his fellow investigators: There had to be a cause of the immunocompromised status of the 5 Los Angeles men. They were, in fact, sick because of something.

Originally known by the derogative term gay-related immune deficiency,¹⁶ the CDC began instead to use acquired immune deficiency syndrome in its September 24, 1982, issue of MMWR,¹⁷ following the appearance of the mysterious virus among additional populations, such as injection drug users and blood transfusion recipients.¹⁸

That was almost 40 years ago, and there still is no vaccine. The lack is especially disheartening in light of the numerous vaccines effective against COVID-19 that were developed over the past year.¹⁹

What challenges are preventing scientists and vaccine developers from getting a leg up on HIV, the virus that does not elicit a protective immune response in the body?

Echoing Halkitis, John Zaia, MD, the Aaron D. Miller and Edith Miller Chair in Gene Therapy at City of Hope, director of its Center for Gene Therapy, and program director of the City of Hope Alpha Stem Cell Clinic, said in an interview with AJMC^® that mutation is a likely cause, due to the RNA nature of the virus. (HIV uses RNA, instead of DNA, to store its genetic information. As such, it is a retrovirus.²⁰)

“RNA replication doesn’t have high fidelity, meaning that mistakes occur while copying the new strand of RNA, whereas DNA replication has high fidelity, meaning that once you copy it, it’s virtually word-for-word precise with only an occasional mutation. So, whenever the virus [HIV] makes 10,000 base pair copies, there’s 1 mistake. But the virus is actually only 10,000 base pairs long in terms of its RNA. So that means there’s about 1 naturally occurring mistake in every new virus. And since there could be billions of new viruses made, there will be literally all these mutations a day, some of which could help the virus survive,” explained Zaia.

Another possible challenge preventing the successful development of an HIV vaccine could be more basic, according to Zaia. Do the vaccines induce mucosal immunity?

Mucosal immunity is a “promising form of immunomodulation for treating certain autoimmune diseases and allergies,” according to prior research.²¹ AIDS, the end stage of HIV infection, is considered an autoimmune disease.²²

“We have a mucosal immunity to many viruses that come in contact with our mucous membranes via nose, throat, etc. Well, HIV would be in the mucous membranes of the genital tract and rectum, [usually],” Zaia said. “So, are these vaccines really making a mucosal immunity where it’s needed? That’s a possible explanation for why the vaccines are not working.”

An effective HIV vaccine may also be hindered because there is not just 1 type of HIV, there are 2: HIV-1 and HIV-2. In addition, HIV-1 has 4 groups of strains: Group M, Group N, Group O, and Group P. On top of that, Group M alone has at least 9 genetically distinct subtypes of HIV-1.²³

So, although in 1984, former HHS Secretary Margaret Heckler was optimistic about the possibility of a vaccine in the following 2 years,²⁴ the trials, research, struggles, failures, and successes continue.

References

1. HIV vaccine Awareness Day 2020. BMC. Accessed May 6, 2021. https://www.biomedcentral.com/p/HIV-Vaccine-Awareness-Day

2. US Military HIV Research Program. Frequently asked questions regarding the RV144 prime-boost HIV vaccine trial. World Health Organization. March 25, 2010. Accessed May 10, 2021. https://www.who.int/immunization/sage/RV144_FAQs.pdf?ua=1

3. HIV vaccine development. National Institute of Allergy and Infectious Diseases. Accessed May 6, 2021. https://www.niaid.nih.gov/diseases-conditions/hiv-vaccine-development

4. HIV vaccine in 2021? Leading experts ‘optimistic’ about ongoing trials. University of Rochester Center for Community Practice. Accessed May 9, 2021. https://www.urccp.org/article.cfm?ArticleNumber=86

5. HVTN 702 clinical trial of an HIV vaccine stopped. News release. UNAIDS; February 4, 2020. Accessed May 9, 2021. https://www.unaids.org/en/resources/presscentre/pressreleaseandstatementarchive/2020/february/20200204_vaccine

6. Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, et al; MOPH-TAVEG Investigators. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med. 2009;361(23):2209-2220. doi:10.1056/NEJMoa0908492

7. History of HIV vaccine research. National Institute of Allergy and Infectious Diseases. Accessed May 18, 2021. https://www.niaid.nih.gov/diseases-conditions/hiv-vaccine-research-history

8. A Study to Assess the Efficacy of a Heterologous Prime/Boost Vaccine Regimen of Ad26.Mos4.HIV and Aluminum Phosphate-Adjuvanted Clade C gp140 in Preventing Human immunodeficiency Virus (HIV) – 1 Infection in Women in Sub-Saharan Africa. NCT03060629. Updated November 25, 2020. Accessed May 10, 2021. https://clinicaltrials.gov/ct2/show/NCT03060629

9. Mngadi K, Buchbinder S; HVTN 705 Protocol Team. HVTN 705/HPX2008: the IMBOKODO study. Accessed May 10, 2021. https://bit.ly/3eUysKa

10. HVTN 706/HPX3002 Mosaico. AVAC: Global Advocacy for HIV Prevention. Updated February 23, 2021. Accessed May 17, 2021. https://www.avac.org/trial/hpx-3002-hvtn-706-mosaico

11. MOSAICO. NCT03964415. Updated May 12, 2021. Accessed May 17, 2021. https://clinicaltrials.gov/ct2/show/NCT03964415

12. Gottlieb MS, Fan PT, Saxon A, Weisman JD, Pozalski I. Pneumocystis pneumonia—Los Angeles. MMWR Morb Mortal Wkly Rep. 1981;30(21):1-36. https://www.cdc.gov/mmwr/preview/mmwrhtml/june_5.htm

13. Pneumocystis pneumonia. CDC. Accessed May 6, 2021. https://www.cdc.gov/fungal/diseases/pneumocystis-pneumonia/index.html

14. Forman R. Michael Gottlieb: the Rutgers alumnus who first identified the deadly disease we now call AIDS. Rutgers Today. November 30, 2015. Accessed May 6, 2021. https://www.rutgers.edu/news/michael-gottlieb-rutgers-alumnus-who-first-identified-deadly-disease-we-now-call-aids

15. Origin of HIV & AIDS. Avert. Updated October 30, 2019. Accessed May 6, 2021. https://bit.ly/3fxb9oZ

16. Altman LK. New homosexual disorder worries health officials. The New York Times. May 11, 1982. Accessed May 6, 2021. https://www.nytimes.com/1982/05/11/science/new-homosexual-disorder-worries-health-officials.html

17. History of AIDS. History/A&E Television Networks. Published July 13, 2017. Updated February 21, 2021. Accessed May 6, 2021. https://www.history.com/topics/1980s/history-of-aids

18. History of HIV/AIDS. Canadian Foundation for AIDS Research. Accessed May 6, 2021. https://canfar.com/awareness/about-hiv-aids/history-of-hiv-aids/

19. AJMC Staff. A timeline of COVID-19 developments in 2020. The American Journal of Managed Care®. January 1, 2021. Accessed May 17, 2021. https://www.ajmc.com/view/a-timeline-of-covid19-developments-in-2020

20. The science of HIV and AIDS—overview. Avert. Updated October 19, 2019. Accessed May 15, 2021. https://www.avert.org/professionals/hiv-science/overview

21. Holmgren J, Czerkinsky C. Mucosal immunity and vaccines. Nat Med. 2005;11(suppl 4):S45-S53. doi:10.1038/nm1213

22. About AIDS. Healio. June 15, 2012. Accessed May 17, 2021. https://bit.ly/2RmTYOS

23. HIV strains and types. Avert. Updated February 26, 2019. Accessed May 17, 2021. https://www.avert.org/professionals/hiv-science/types-strains

24. Desrosiers RC. HIV/AIDS vaccine: why don't we have one after 37 years, when we have several for COVID-19 after a few months? Yahoo!News. May 17, 2021. Accessed May 18, 2021. https://news.yahoo.com/hiv-aids-vaccine-why-dont-192203679.html