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Vaccine

A Vaccine Against COVID-19 Would Be the Latest Success in a Long Scientific History

BY JEFFREY KLUGER MAY 15, 2020 8:30 AM EDT

Here’s betting you wouldn’t want anyone blowing smallpox scabs up your nose. But you might feel differently if you lived in 15th century China.

Long ago, the Chinese recognized that people who had contracted smallpox once were immune to reinfection. They came up with the idea of preserving scabs from individuals who had suffered mild cases, drying them out, crushing them to a powder and blowing them up the nostril. For boys it was the right nostril, for girls it was the left because, well, 15th century.

That is how the story of vaccines usually begins, though that version is decidedly incomplete. For one thing, it’s unclear how effective the early efforts at inoculation were. For another, no one knows just when the practice began, with some accounts pegging the date as long ago as 200 BCE. Scattered, less reliable stories of similar vaccination efforts have been reported in India and Africa too, but the evidence there is much thinner. So hat tip to Ming dynasty China, which apparently got the vaccine bandwagon rolling.

Vaccination is much on the world’s collective mind today as researchers at pharmaceutical companies and universities race to develop a way to prevent the continued spread of COVID-19. The most optimistic projections suggest a vaccine could be in hand by January; other, more cautious predictions see a wait of at least 18 months./.../

Edward Jenner

WRITTEN BY: 

• Lester S. King

LAST UPDATED: May 13, 2020 See Article History

Edward Jenner, (born May 17, 1749, Berkeley, Gloucestershire, England—died January 26, 1823, Berkeley), English surgeon and discoverer of vaccination for smallpox.

Jenner was born at a time when the patterns of British medical practice and education were undergoing gradual change. Slowly the division between the Oxford- or Cambridge-trained physicians and the apothecaries or surgeons—who were much less educated and who acquired their medical knowledge through apprenticeship rather than through academic work—was becoming less sharp, and hospital work was becoming much more important.

Jenner was a country youth, the son of a clergyman. Because Edward was only five when his father died, he was brought up by an older brother, who was also a clergyman. Edward acquired a love of nature that remained with him all his life. He attended grammar school and at the age of 13 was apprenticed to a nearby surgeon. In the following eight years Jenner acquired a sound knowledge of medical and surgical practice. On completing his apprenticeship at the age of 21, he went to London and became the house pupil of John Hunter, who was on the staff of St. George’s Hospital and was one of the most prominent surgeons in London. Even more important, however, he was an anatomist, biologist, and experimentalist of the first rank; not only did he collect biological specimens, but he also concerned himself with problems of physiology and function.

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Edward Jenner: smallpox vaccinationEdward Jenner vaccinating his child against smallpox; coloured engraving.Wellcome Library, London (CC BY 4.0)

Vaccine Effectiveness

After Pasteur’s time, a widespread and intensive search for new vaccines was conducted, and vaccines against both bacteria and viruses were produced, as well as vaccines against venoms and other toxins. Through vaccination, smallpox was eradicated worldwide by 1980, and polio cases declined by 99 percent. Other examples of diseases for which vaccines have been developed include mumps, measles, typhoid fever, cholera, plague, tuberculosis, tularemia, pneumococcal infection, tetanus, influenza, yellow fever, hepatitis A, hepatitis B, some types of encephalitis, and typhus—although some of those vaccines are less than 100 percent effective or are used only in populations at high risk. Vaccines against viruses provide especially important immune protection, since, unlike bacterial infections, viral infections do not respond to antibiotics.

historical mass vaccination programs in the United StatesIn the United States, mass vaccination programs carried out against diphtheria, polio, and measles have almost eradicated these diseases from the population. The graphs indicate the years the vaccines were introduced. Data source: U.S. Bureau of the Census, Historical Statistics of the United States: Colonial Times to 1970 (CD-ROM ed., 1997).Encyclopædia Britannica, Inc.

Vaccine Types

The challenge in vaccine development consists in devising a vaccine strong enough to ward off infection without making the individual seriously ill. To that end, researchers have devised different types of vaccines. Weakened, or attenuated, vaccines consist of microorganisms that have lost the ability to cause serious illness but retain the ability to stimulate immunity. They may produce a mild or subclinical form of the disease. Attenuated vaccines include those for measles, mumps, polio (the Sabin vaccine), rubella, and tuberculosis. Inactivated vaccines are those that contain organisms that have been killed or inactivated with heat or chemicals. Inactivated vaccines elicit an immune response, but the response often is less complete than with attenuated vaccines. Because inactivated vaccines are not as effective at fighting infection as those made from attenuated microorganisms, greater quantities of inactivated vaccines are administered. Vaccines against rabies, polio (the Salk vaccine), some forms of influenza, and cholera are made from inactivated microorganisms. Another type of vaccine is a subunit vaccine, which is made from proteins found on the surface of infectious agents. Vaccines for influenza and hepatitis B are of that type. When toxins, the metabolic by-products of infectious organisms, are inactivated to form toxoids, they can be used to stimulate immunity against tetanus, diphtheria, and whooping cough (pertussis).

vaccinationThe basic strategies behind the use of vaccines to prepare the human immune system to deal with harmful pathogens. Adjuvants, such as aluminum, are incorporated into vaccines to hasten the body's immune response.© MinuteEarth (A Britannica Publishing Partner)See all videos for this article

In the late 20th century, advances in laboratory techniques allowed approaches to vaccine development to be refined. Medical researchers could identify the genes of a pathogen (disease-causing microorganism) that encode the protein or proteins that stimulate the immune response to that organism. That allowed the immunity-stimulating proteins (called antigens) to be mass-produced and used in vaccines. It also made it possible to alter pathogens genetically and produce weakened strains of viruses. In that way, harmful proteins from pathogens can be deleted or modified, thus providing a safer and more-effective method by which to manufacture attenuated vaccines.

Recombinant DNA technology has also proven useful in developing vaccines to viruses that cannot be grown successfully or that are inherently dangerous. Genetic material that codes for a desired antigen is inserted into the attenuated form of a large virus, such as the vaccinia virus, which carries the foreign genes “piggyback.” The altered virus is injected into an individual to stimulate antibody production to the foreign proteins and thus confer immunity. The approach potentially enables the vaccinia virus to function as a live vaccine against several diseases, once it has received genes derived from the relevant disease-causing microorganisms. A similar procedure can be followed using a modified bacterium, such as Salmonella typhimurium, as the carrier of a foreign gene.

Vaccines against human papillomavirus (HPV) are made from viruslike particles (VLPs), which are prepared via recombinant technology. The vaccines do not contain live HPV biological or genetic material and therefore are incapable of causing infection. Two types of HPV vaccines have been developed, including a bivalent HPV vaccine, made using VLPs of HPV types 16 and 18, and a tetravalent vaccine, made with VLPs of HPV types 6, 11, 16, and 18.

Gardasil human papillomavirus vaccineGardasil, the trade name of a human papillomavirus (HPV) vaccine, protects against four different types of HPV that are responsible for cervical cancer and genital warts.Garo—Phanie/AGE fotostock

Another approach, called naked DNA therapy, involves injecting DNA that encodes a foreign protein into muscle cells. The cells produce the foreign antigen, which stimulates an immune response.

Table Of Vaccine-Preventable Diseases

disease	year
*Vaccine recommended for universal use in U.S. children. For smallpox, routine vaccination was ended in 1971.
**Vaccine developed (i.e., first published results of vaccine usage).
***Vaccine licensed for use in United States.
smallpox*	1798**
rabies	1885**
typhoid	1896**
cholera	1896**
plague	1897**
diphtheria*	1923**
pertussis*	1926**
tetanus*	1927**
tuberculosis	1927**
influenza	1945***
yellow fever	1953***
poliomyelitis*	1955***
measles*	1963***
mumps*	1967***
rubella*	1969***
anthrax	1970***
meningitis	1975***
pneumonia	1977***
adenovirus	1980***
hepatitis B*	1981***
Haemophilus influenzae type b*	1985***
Japanese encephalitis	1992***
hepatitis A	1995***
varicella*	1995***
Lyme disease	1998***
rotavirus*	1998***
human papillomavirus	2006
dengue fever

Vaccine-preventable diseases in the United States, presented by year of vaccine development or licensure.

disease	year
*Vaccine recommended for universal use in U.S. children. For smallpox, routine vaccination was ended in 1971.
**Vaccine developed (i.e., first published results of vaccine usage).
***Vaccine licensed for use in United States.

Herd Immunity

EDITORIAL

COVID-19: Health Equity—A New “Herd Immunity”

David R. Williams, PhD, MPH; Lisa A. Cooper, MD, MPH

“Herd Immunity” Redefined

The striking racial/ethnic disparities reported for COVID-19 infection, testing, and disease burden are a clear reminder that failure to protect the most vulnerable members of society not only harms them but also increases the risk of spread of the virus, with devastating health and economic consequences for all. COVID-19 disparities are not the fault of those who are experiencing them, but rather reflect social policies and systems that create health disparities in good times and inflate them in a crisis. The US must develop a new kind of “herd immunity,” whereby resistance to the spread of poor health in the population occurs when a sufficiently high proportion of individuals, across all racial, ethnic, and social class groups, are protected from and thus “immune” to negative social determinants.

orage de cytokines

Avis de tempête immunitaire dans les cas graves de Covid-19

CORONAVIRUS

Un phénomène d’hyper-inflammation de l’organisme, appelé «orage de cytokines», pourrait jouer un rôle important dans les cas sévères de Covid-19. Des pistes thérapeutiques sont à l’étude

Comment expliquer, dans l’épidémie actuelle de Covid-19, que certaines personnes infectées par le SARS-CoV-2 ne présentent pas ou peu de symptômes, alors que d’autres développent une forme aiguë de la maladie, y compris des individus en apparente bonne santé?

La réponse pourrait bien se trouver au sein de notre système immunitaire, et plus particulièrement dans sa façon de répondre aux infections. L’une des particularités du nouveau coronavirus étant sa capacité à engendrer un phénomène appelé «orage de cytokines», à savoir la libération massive de molécules impliquées dans le contrôle de l’immunité. Cette forme d’hyper-inflammation serait ainsi pointée, selon un article publié mi-mars dans The Lancet par une équipe anglaise, comme un facteur pouvant non seulement expliquer la sévérité mais aussi la mortalité liées au nouveau coronavirus.

New Immunotherapy

New Immunotherapy Treatment Removes All Tumors In Woman With Advanced Metastatic Breast Cancer

Victoria ForsterContributor 

Alerta do AMICOR Paulo P Teixeira

Cancer research scientist and childhood cancer survivor.

T-cells extracted from a tumor, expanded and then re-introduced into the body have resulted in the disappearance of tumors in a woman with metastatic breast cancer.

Research published today in Nature Medicine by scientists at the National Cancer Institute (NCI) has described a new immunotherapy approach, which led to a complete disappearance of tumors in a woman with advanced metastatic breast cancer who only had months to live.

The findings show how naturally-occurring tumor infiltrating lymphocytes (TILs) were extracted from the patient's tumor, grown outside of her body to boost their numbers and injected back into the patient to tackle the cancer. The patient had previously received several treatments including hormone therapies and chemotherapy, but nothing had stopped the cancer progressing. After the treatment, all of the patient’s tumors disappeared and 22 months later, she is still in remission.

Researchers are particularly enthusiastic about the potential of TILs to treat a group of cancers termed ‘common epithelial cancers’, which include those of the colon, rectum, pancreas, breast and lung, together accounting for 90% of all deaths due to cancer in the U.S, around 540,000 people annually, most of these from metastatic disease.

“Once these cancers spread, most people die. We have no effective ways of eliminating metastatic cancers,” said Steven A. Rosenberg, M.D., Ph.D., chief of the Surgery Branch at NCI’s Center for Cancer Research (CCR).

The first step of this new treatment approach is to DNA sequence the tumor.  In the case of this patient, the researchers found 62 mutations in the breast tumor cells. The second is to isolate TILs, which are present naturally in 80% of epithelial cell tumors, but in tiny amounts, not substantial enough to attack the tumor. These are then analyzed for their ability to recognize and target the mutated proteins on the tumor.  In the case of the metastatic breast cancer patient, the researchers found TILs that recognized four of the mutant proteins.

“We isolate these lymphocytes from the tumor, grow them in large numbers and give them back to their patients. We made around 90 billion cells for this patient,” said Rosenberg.

While the TILs were being grown, the patient was also treated with PD-1 blocking, immunotherapy agent Keytruda to modify the immune system so other immune cells wouldn’t interfere with the TILs when they were infused back into the patient after being greatly expanded.

“We are developing patients own lymphoblasts into treatments, they are natural T-cells, not genetically engineered. This is the most highly personalized treatment you can imagine," said Rosenberg.

The metastatic breast cancer patient is not the only person to have been successfully treated using this method. Rosenberg and colleagues have also had impressive results using TILs to treat an additional three different types of metastatic cancer; colorectal, bile duct and cervical.

“These treatments have the potential to treat patients with any cancer,” claims Rosenberg.

Although the results are undoubtedly promising, especially due to the low levels of toxicity patients have experienced compared to conventional chemotherapies, cancers often develop resistance to treatments and often metastases may have different mutations than the original tumor.

So will patients easily develop resistance to TILs?

“It is ironic that the very mutations that caused the cancer may be the Achilles heel that enables the destruction of the cancer. It’s really important to treat for different mutations at once,” said Rosenberg.

This oddly enough is one advantage of many old chemotherapy drugs compared to newer personalized treatments. Because many indiscriminately pepper the genome with carpet-bombing style damage, it can make it more difficult for a cancer cell to evolve resistance to them. Picking TILs that target just a single or small number of mutated proteins on the tumor may increase the chance that the cancer will be able to evolve resistance. More research is needed into this and also how to identify the which mutations on cancer cells are possible targets for TILs.

If larger trials support these excellent preliminary results, producing individualized T-cell therapies for each patient is undoubtedly a logistical and technical challenge, requiring specialist laboratories and expertise. How practical is it to produce a completely personalized therapy for each patient?

“People said that about CAR T-cells too. If you find something that works for patients, whether it’s complicated or not, the genius of industry will find a way to make it work,” said Rosenberg.

Indeed, several companies are already running trials for TIL therapies, including Bristol-Myers Squibb and Iovance Biotherapeutics, the latter of which specifically focuses on TILs. Clinical trials of TILs are currently underway for melanoma, cervical, lung and even notoriously hard-to-treat glioblastoma and pancreatic cancer, amongst others.

“This is a change in our thinking about what might be needed to treat these cancers. A new paradigm for cancer therapy,” said Rosenberg.

Very rarely do entirely new methods of treating cancer enter the fray with such dramatic results as those shown for TILs in these individual cases. What is badly needed now are the results from the underway larger scale clinical trials and continual monitoring of patients who have been successfully treated to ensure their cancers do not relapse.

“This is an illustrative case report that highlights, once again, the power of immunotherapy,” said Tom Misteli, Ph.D., director of CCR at NCI. “If confirmed in a larger study, it promises to further extend the reach of this T-cell therapy to a broader spectrum of cancers.”

Victoria Forster

I am a postdoctoral research scientist focusing on childhood cancers and new, targeted cancer therapies. As a survivor of childhood leukemia myself, I am a determined a...

 

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