We can get a COVID-19 vaccine in months but not one for HIV? - Escanaba Daily Press

Posted: 22 May 2021 12:04 AM PDT

Metro photo Vaccines to protect against COVID-19 were create and implemented at speeds unheard of prior to the pandemic. So why, after 37 years, isn't there a vaccine for HIV?

The Conversation is an independent and nonprofit source of news, analysis and commentary from academic experts. Today's piece is by Ronald C. Desrosiers, of the University of Miami.

(THE CONVERSATION) — Smallpox has been eradicated from the face of the Earth following a highly effective, worldwide vaccination campaign. Paralytic poliomyelitis is no longer a problem in the U.S. because of development and use of effective vaccines against the poliovirus. In current times, millions of lives have been saved because of rapid deployment of effective vaccines against COVID-19. And yet, it has been 37 years since HIV was discovered as the cause of AIDS, and there is no vaccine. Here I will describe the difficulties facing development of an effective vaccine against HIV/AIDS.

I am a professor of pathology at the University of Miami Miller School of Medicine. My laboratory is credited with the discovery of the monkey virus called SIV, or simian immunodeficiency virus. SIV is the close monkey relative of the virus that causes AIDS in humans – HIV, or human immunodeficiency virus. My research has contributed importantly to the understanding of the mechanisms by which HIV causes disease and to vaccine development efforts.

HIV vaccine development efforts have come up short

Vaccines have unquestionably been society's most potent weapon against viral diseases of medical importance. When the new disease AIDS burst onto the scene in the early 1980s and the virus that caused it was discovered in 1983-84, it was only natural to think that the research community would be able to develop a vaccine for it.

At a now famous press conference in 1984 announcing HIV as the cause of AIDS, then U.S. Secretary of Health and Human Services Margaret Heckler predicted that a vaccine would be available in two years. Well, it is now 37 years later and there is no vaccine. The rapidity of COVID-19 vaccine development and distribution puts the lack of an HIV vaccine in stark contrast. The problem is not failure of government. The problem is not lack of spending. The difficulty lies in the HIV virus itself. In particular, this includes the remarkable HIV strain diversity and the immune evasion strategies of the virus.

So far there have been five large-scale Phase 3 vaccine efficacy trials against HIV, each at a cost of over US$100 million. The first three of these failed quite convincingly; no protection against acquisition of HIV infection, no lowering of viral loads in those who did become infected. In fact, in the third of these trials, the STEP trial, there was a statistically significant higher frequency of infection in individuals who had been vaccinated.

The fourth trial, the controversial Thai RV144 trial, initially reported a marginal degree of successful protection against the acquisition of HIV infection among vaccinated individuals. However, a subsequent statistical analysis reported that there was less than a 78% chance that the protection against acquisition was real.

A fifth vaccine trial, the HVTN 702 trial, was ordered to confirm and extend the results of the RV144 trial. The HVTN702 trial was halted early because of futility. No protection against acquisition. No lowering of viral load. Ouch.

The complexity of HIV

What is the problem? The biological properties that HIV has evolved make development of a successful vaccine very, very difficult. What are those properties?

First and foremost is the continuous unrelenting virus replication. Once HIV gets its foot in the door, it's "gotcha." Many vaccines do not protect absolutely against the acquisition of an infection, but they are able to severely limit the replication of the virus and any illness that might result. For a vaccine to be effective against HIV, it will likely need to provide an absolute sterilizing barrier and not just limit viral replication.

HIV has evolved an ability to generate and to tolerate many mutations in its genetic information. The consequence of this is an enormous amount of variation among strains of the virus not only from one individual to another but even within a single individual. Let's use influenza for a comparison. Everyone knows that people need to get revaccinated against influenza virus each season because of season-to-season variability in the influenza strain that is circulating. Well, the variability of HIV within a single infected individual exceeds the entire worldwide sequence variability in the influenza virus during an entire season.

What are we going to put into a vaccine to cover this extent of strain variability?

HIV has also evolved an incredible ability to shield itself from recognition by antibodies. Enveloped viruses such as coronaviruses and herpes viruses encode a structure on their surface that each virus uses to gain entry into a cell. This structure is called a "glycoprotein," meaning that it is composed of both sugars and protein. But the HIV envelope glycoprotein is extreme. It is the most heavily sugared protein of all viruses in all 22 families. More than half the weight is sugar. And the virus has figured out a way, meaning the virus has evolved by natural selection, to use these sugars as shields to protect itself from recognition by antibodies that the infected host is trying to make. The host cell adds these sugars and then views them as self.

These properties have important consequences relevant for vaccine development efforts. The antibodies that an HIV-infected person makes typically have only very weak neutralizing activity against the virus. Furthermore, these antibodies are very strain-specific; they will neutralize the strain with which the individual is infected but not the thousands and thousands of other strains circulating in the population. Researchers know how to elicit antibodies that will neutralize one strain, but not antibodies with an ability to protect against the thousands and thousands of strains circulating in the population. That's a major problem for vaccine development efforts.

HIV is continually evolving within a single infected individual to stay one step ahead of the immune responses. The host elicits a particular immune response that attacks the virus. This puts selective pressure on the virus, and through natural selection a mutated virus variant appears that is no longer recognized by the individual's immune system. The result is continuous unrelenting viral replication.

So, should we researchers give up? No, we shouldn't. One approach researchers are trying in animal models in a couple of laboratories is to use herpes viruses as vectors to deliver the AIDS virus proteins. The herpes virus family is of the "persistent" category. Once infected with a herpes virus, you are infected for life. And immune responses persist not just as memory but in a continually active fashion. Success of this approach, however, will still depend on figuring out how to elicit the breadth of immune responses that will allow coverage against the vast complexity of HIV sequences circulating in the population.

Another approach is to go after protective immunity from a different angle. Although the vast majority of HIV-infected individuals make antibodies with weak, strain-specific neutralizing activity, some rare individuals do make antibodies with potent neutralizing activity against a broad range of HIV isolates. These antibodies are rare and highly unusual, but we scientists do have them in our possession.

Also, scientists have recently figured out a way to achieve protective levels of these antibodies for life from a single administration. For life! This delivery depends on a viral vector, a vector called adeno-associated virus. When the vector is administered to muscle, muscle cells become factories that continuously produce the potent broadly neutralizing antibodies. Researchers have recently documented continuous production for six and a half years in a monkey.

We are making progress. We must not give up.

— — —

This article is republished from The Conversation under a Creative Commons license. Read the original article here: https://theconversation.com/hiv-aids-vaccine-why-dont-we-have-one-after-37-years-when-we-have-several-for-covid-19-after-a-few-months-160690.

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Monday After: Remembering the introduction in Stark County of the polio vaccine - Canton Repository

Posted: 17 May 2021 02:52 AM PDT

Gary Brown | Special to The Canton Repository

The cure for a disease that was crippling our children arrived in Stark County 66 years ago.

"April 12 Verdict on Vaccine Is Seen As Death Knell of Widespread Polio," a front-page headline in The Canton Repository reported on April 3, 1955, looking ahead to the upcoming day when a press conference was expected to confirm the effectiveness of the anti-polio vaccine developed by Dr. Jonas E. Salk of Pittsburgh. "Go-Ahead Signal Is Expected to All-Out Attack."

And, indeed, little more than a week later, an announcement said that results of testing on 400,000 children done in the summer of 1954 by Dr. Thomas Francis Jr. of the University of Michigan verified that the vaccine developed by his former student, Dr. Jonas E. Salk of Pittsburgh, was "80 to 90% effective in preventing paralytic polio."

"Dr. Francis' official report declared the vaccine had produced an 'extremely successful effect' among children with bulbar polio, the most dangerous type," the Repository reported following the press conference.

At the press conference, Dr. Salk "declared he is sure the vaccine is potentially almost 100 percent effective and can bring complete triumph over polio and its lieutenants of terror and tragedy."

"There is no doubt that children now can be vaccinated successfully to end the threat of polio and the anxiety it causes every year," reported Alton L. Blakeslee, Associated Press science reporter," in an article published at the top of the front page in the Repository on April 12, 1955. "The vaccine was found incredibly safe and with only .4 of 1% of children suffering minor reactions. So-called 'major reactions' were almost completely lacking."

The period of protection provided by the vaccine "appears reasonably good," said the Associated Press story, noting that announcements at the press conference estimated the effectiveness of the three-shot vaccine series as being "maintained with but moderate decline after five months."

"Dr. Salk urged that children this year be given only two shots of vaccine in order to step up the effectiveness of the vaccine," AP reported. "He said the shots should be spaced two to four weeks apart with the third one delayed for at least seven months afterward."

Shots begin in Stark County

More than 13,000 first- and second-grade pupils in public, parochial and private schools in Canton, Massillon, and Alliance — whose parents signed consent forms — were the first in Stark County to receive the Salk polio vaccine free of charge in Stark County.

Cost of the vaccine was being paid for by the National Foundation for Infantile Paralysis, which had purchased $9 million worth of doses long before the vaccine even proved effective. Leo Berger, Stark County chairman of the foundation locally, said the series of three shots would cost the foundation about $1 per child, paid for by funds raised during the local chapter 's annual March of Dimes campaign.

"That liquid may well be the most powerful friend ever created for children," reported the Repository in a secondary story to the Salk vaccine press conference reporting. "It will guard and protect against a crippler and a killer."

Canton children would begin getting their shots as early as April 20, 1955, and the initial "get-a-shot" campaign would continue through June.

Until then the city schools and Stark County Health Department would store vaccine in refrigerators loaned by the Canton Hardware Co.

Throughout Ohio, similar vaccine efforts were being undertaken, directed by state health officials.

"Dr. Ralph E. Dwork, state director of health, said machinery has been completed for the immediate distribution of the vaccine upon its arrival in Ohio," an Associated Press article reported. "There are 440,540 school children in Ohio eligible to receive the vaccine."

"Dr. Dwork said that the first shipment of vaccine would contain enough material to cover the first two inoculations," AP reported. "A subsequent shipment would supply the vaccine for the third shot."

What was the vaccine?

What exactly was this vaccine, which was being produced by a handful of pharmaceutical companies? And how did it work?

Another article in the Repository explained that the medical marvel was "a red liquid containing billions of dead viruses, of all three types, which can cause paralysis in humans."

"The killed viruses cannot cause sickness, but can stimulate the receiver to make antibodies."

Salk explained at the introduction of the vaccine that the first two shots stimulated the production of the antibodies in the bloodstream of a child, and those antibodies turned the immune system into a "cocked revolver" awaiting signs of virus needing to be killed.

"The booster shot given at least seven months later serves as a trigger to produce remarkably high amounts of antibodies," the article reported. "He said natural exposure to polio, if it occurs after the first two shots, also acts as a trigger to explode the antibody mechanism into action."

Medical experts urged that the vaccine go to the "most vulnerable," young children and pregnant women, with the aim to "hit polio hardest by inoculating those most susceptible."

"Adults have less need for it," the article explained. "By about age 18, most of us have been exposed already to one or more of the three dangerous types of virus and have become immune."

Some parents were hesitant

Still, in the spring and summer of 1955, some parents were hesitating in having their children inoculated.

The cause, at least in part, was called the "Cutter incident."

"In 1955, some batches of polio vaccine given to the public contained live polio virus, even though they had passed required safety testing," recalled a posting about "vaccine safety" at the website for the Centers for Disease Control and Prevention. "Over 250 cases of polio were attributed to vaccines produced by one company: Cutter Laboratories. This case, which came to be known as the Cutter Incident, resulted in many cases of paralysis. The vaccine was recalled as soon as cases of polio were detected.

"The cutter incident was a defining moment in the history of vaccine manufacturing and government oversight of vaccines, and led to the creation of a better system of regulating vaccines. After the government improved this process and increased oversight, polio vaccinations resumed in the fall of 1955."

At that same time, another polio vaccine — developed by Russian-born Dr. Albert Sabin of the University of Cincinnati College of Medicine — was on the horizon.

"Around the same time that Salk began his work on a killed-virus vaccine, Sabin began work on an attenuated live-virus vaccine," explained an article published online at the Science History Institute's website sciencehistory.org. "Sabin felt that an oral vaccine would be superior to an injection, as it would be easier to administer. He began to grow and test many virus strains in animals and tissue cultures and eventually found three mutant strains of the virus that appeared to stimulate antibody production without causing paralysis. Sabin then tested these strains on humans: his subjects included himself and his family, research associates, and prisoners from the nearby Chillicothe Penitentiary."

Late in the 1950s, the Science History Institute noted, Sabin contracted with the pharmaceutical company Pfizer to produce his live-virus vaccine in its British facilities.

"Sabin's live-virus, oral polio vaccine (administered in drops or on a sugar cube) soon replaced Salk's killed virus, injectable vaccine in many parts of the world. In 1994 the WHO (World Health Organization) declared that naturally occurring poliovirus had been eradicated from the Western Hemisphere owing to repeated mass immunization campaigns with the Sabin vaccine in Central and South America."

Live Versus Killed

The Institute's information went on to say that Sabin "staunchly defended his live-virus vaccine" during his lifetime, "refusing to believe any evidence that it could cause paralytic poliomyelitis.

"Salk, for his part, believed that killed-virus vaccine produced equivalent protection in individuals and in communities without any risk for causing paralysis," the Institute said. "Despite Sabin's belief, the risk for paralysis from the live-virus vaccine does exist, although it is slight.

"In 1999 a federal advisory panel recommended that the United States return to Salk's vaccine because it cannot accidentally cause polio. On the basis of a decade of additional evidence, this recommendation was reconfirmed in 2009."

The "inactivated poliovirus vaccine (IPV)," or the killed-virus vaccine, remains the only anti-polio vaccine in use in the United States since the turn of the 21st century.

Reach Gary at gary.brown.rep@gmail.com.

On Twitter: @gbrownREP

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