Will the vaccine work?

August 12, 2020 0 By FM

Developing a vaccine against COVID-19 infection is perhaps the most urgent mission in the annals of modern medical science.

Thousands of researchers in more than 30 countries are working on over 600 projects to develop an effective vaccine shot that could shield mankind from the SARS-CoV-2 contagion that has left none unaffected.

The emergent scenario compelled researchers to drastically cut short development timelines, which could otherwise stretch on for years or even decades, and come up with a handful of promising vaccine candidates within a span of a few months.

To get a set of candidate vaccines ready to go into phase 3 trials within three months of the discovery of the new virus is unprecedented in medical history.

As of July, four developers have released detailed safety data from human trials showing that their experimental vaccines produced only minor side effects in humans. The results also indicate that all four vaccines produced a strong immune response.

One of the vaccines, developed by researchers at Oxford University in coordination with Anglo-Swedish drug major AstraZeneca, is considered the frontrunner. Its doses have already been received by more than 10,000 trial participants in Britain, Brazil and South Africa. Another phase III test involving 30,000 participants has begun in the US.

On the high road to immunity

Even as the entire world seems to be banking on a vaccine to put an end to the devastation caused by the pandemic, critics say there are several important questions that are still unanswered.

Of these, concerns about the safety of these rapidly developed vaccine candidates have largely been set aside by voluminous data released from early human studies. The Oxford vaccine, for example, has already been tested before.

Therefore, the crucial question that remains is how effective a vaccine would be and whether it can trigger an immune response that protects against COVID-19. And if it can, how long its protection would last. 

Some experts believe that it is highly unlikely that any of these vaccines would be 100% effective. 

For their part, Oxford University researchers have said that the interim phase I/II data for their vaccine showed immune responses in line with what they expect will be associated with protection against the SARS-CoV-2 virus, although these numbers need to be confirmed by a rigorous clinical trial programme.

Vaccines generally work by prompting the body to produce antibodies that neutralise the virus, thereby blocking its entry into the cells. But all vaccines do not cause the production of these neutralising antibodies that confer the so-called sterilising immunity — an immune response that completely eliminates the infection. 

When Oxford researchers announced the final results of a monkey study in mid-May, it was found that the nasal swabs of the six monkeys challenged by the virus 28 days after administering the vaccine tested positive. This significant finding, critics argue, is indicative of the fact that the animals could still spew the virus and infect others, although none of them showed any signs of developing pneumonia in their lungs after being bombarded by an overwhelming dose of the pathogen through their eyes, nostrils, mouth and trachea.  

William Haseltine, a well-known HIV researcher and a former professor at Harvard Medical School, was among the ones who were quick to point out this aspect. He said the Oxford vaccine looked like it would be only partially protective, because it didn’t generate high levels of neutralising antibodies that protect cells against infection.

That in turn leads to the question of what is the level of antibodies required to fully protect a person from catching COVID-19? Unfortunately, nobody knows the answer till now. 

According to Prof Haseltine, the vaccine could work but not as desired. It might still require a booster, especially for older people. Boosting the vaccine with additional dosing or by other means can be risky, including potential toxicities and side-effects.

Another, similar study using Moderna’s mRNA candidate in eight Rhesus macaques found that no replicating virus was detectable in the lungs of seven out of eight macaques in the vaccinated groups. The researchers injected two doses — of 10-µg or 100-µg strengths – into the animals 28 days apart.

This is the first time an experimental COVID-19 vaccine tested in nonhuman primates has been shown to produce such rapid viral control in the upper airway, the investigators wrote, while publishing the results in The New England Journal of Medicine.

Vanishing antibodies; T-cells move centre-stage

Vaccine developers, however, contend that it could simply be distracting to bank solely on the generation of neutralising antibodies to determine the level of efficacy of a vaccine, even though eliciting them is the basis for most successful vaccines.

The number of antibodies is often a surrogate for the T-cell number. T lymphocytes, one of the major components of the adaptive immune system, are able to kill virus-infected cells and unleash fresh immune attacks against invading microbes by activating other immune cells. Memory T cells, at the same time, remember past diseases for decades.

Antibodies, in contrast, wane after a certain period of time. In COVID-19 patients, antibodies disappear after 8 weeks following recovery, according to a small Chinese study conducted on people with mild disease. What this doesn’t mean is that since antibodies are fewer in number, there is no immunity.

Emerging data suggest that T-cells, which currently get less attention from vaccinologists, may play a crucial role in responses to SARS-CoV-2. If one gets a strong T-cell response, the individual doesn’t require a high neutralising antibody titre to achieve protection. If a vaccine can elicit a combination of neutralising antibodies and T-cells, it could better protect against the disease.

Strangely enough, some people who were able to recover from COVID-19 do not produce antibodies. A recent German study offers an explanation for this strange phenomenon. The researchers have found that T-cells which offered protection from older coronavirus can strengthen the immune response to COVID-19.

In short, if one can get sufficient protection from T-cells immunity, then the body never has to create antibodies.

The relative importance of those two arms of the immune response is in SARS, MERS, and COVID-19 is yet to be figured out.

Oxford-AstraZeneca, Pfizer-BioNTech, as well as China’s CanSino Biologics all hailed the presence of T cells in vaccine recipients as an indicator of the effectiveness of their experimental vaccines.

Another area of uncertainty is how strong the immune response needs to be to achieve protection in people of any age.

A research preview by Lihong Liu et al published in July found that low doses of antibodies could block the new virus’s ability to infect cells. The researchers used a diverse group of antibodies sourced from the convalescent plasma of severely ill patients. 

The lack of understanding of the precise nature of the immune responses that protect against COVID-19, is obviously the reason why experts caution against comparing early-phase data on the immune response. 

“There is a critical need for an improved understanding of the immune response following natural infection in order to develop a vaccine to prevent transmission and to identify and develop strategies to distinguish vaccine-elicited responses from those induced by SARS-CoV-2 natural infection,” avers Shelly Karuna MD, Co-Chair for the HVTN 405/HPTN 1901 study conducted by HIV Vaccine Trials Network (HVTN) Leadership Operations Center based at the Fred Hutchinson Cancer Research Center, Seattle.

This study proposes to describe the body’s natural immune responses to SARS-CoV-2, thus illuminating the path to the development and testing of a safe and effective vaccine.

According to Dr Karuna, the HVTN 405/HPTN 1901 study, which is underway at clinical trial sites across North and South America, will explore the variety of immune signatures after recovery from natural SARS-CoV-2 infection across a range of clinical phenotypes.

Data generated from this cohort of 400 participants aged 18 and older who tested positive for SARS-CoV-2 and have since recovered will facilitate the development and formal qualification of several immunologic assays, including characterising the immune responses to SARS-CoV-2 infection.

Furthermore, the study will generate highly standardised datasets of SARS-CoV-2-specific adaptive immunity; identify immune markers of COVID-19 disease severity and duration and shed light on the impact of demographic variables such as age and gender. Perhaps most importantly, it may identify antibody responses that could differentiate a SARS-CoV-2 infection from vaccination. All of this will inform future vaccine and monoclonal antibody design and testing, she added.

Nevertheless, the performance of vaccines and whether they will help end the pandemic will be determined by much larger trials on a more diverse group, particularly older people. 

Surmounting challenges

The tricky new coronavirus poses several challenges that defy researchers’ efforts to develop an effective vaccine.

The latest research shows that certain mutations in the spike protein of the virus can help them evade neutralising antibodies. This suggests that treatment ‘cocktails’ of multiple neutralising antibodies, each recognising a different part of the spike protein, may be
required to stop the virus from evolving resistance.

Already, the world’s leading vaccine makers like GSK have indicated that more than one vaccine would be necessary to address the needs of varying demographic groups and differing epidemiological profiles.

Scientists around the world are also worried about the horror of antibody dependent enhancement, or ADE. The phenomenon, which makes a viral infection much more acute, was detected in a SARS infection, while testing for a vaccine in 2002-03. 

In recent years, Dengvaxia, Sanofi’s dengue vaccine, was found to exacerbate symptoms in some who received it.

Frequent surges and declines of the virus around the world are yet another hurdle. The right time to test the efficacy of a vaccine in a particular region, researchers say, is when the caseload is in a waxing phase. But usually, case numbers start to wane soon after a surge in most places, making it difficult to continue with the studies. Hence, they have to run multiple trials in multiple locations as a way out. 

Vac shots in billions—A logistical nightmare

The key question today is not whether a successful vaccine can be devised, but how many doses can be produced rapidly, according to the head of Sanofi, one of the world’s leading vaccine makers.

Producing billions of doses of the vaccine is certainly a huge challenge for manufacturers. The scale-up of any process is really cumbersome, especially with biological material.

Pharmaceutical companies have to scale up for a product launch that may be the biggest in modern history; that too at a time when the global economy is heading to a downturn.

Supply chains are not ready yet for the mammoth task of shipping billions of doses of the vaccine. The freight industry, cargo aircraft and container ships have already been hit by the protracted pandemic.

Moreover, vaccine supply chains are more complex. A vaccine will be destroyed if left on the tarmac for a couple of days, unlike other medical supplies. 

Developers are usually hesitant to invest in capacity building for experimental vaccines due to their high failure rate. 

AstraZeneca agreed to be responsible for the worldwide distribution and manufacturing of the Oxford vaccine. The company is signing production agreements with partners worldwide, including Oxford Biomedica Plc. It has also forged a licensing deal with Serum Institute of India, the world’s largest vaccine producer by number of doses, to manufacture a billion doses for developing and middle-income countries.

It is also setting up independent supply chains within countries to prevent delays at national borders, reports show.

Some of the most prominent players, such as Johnson & Johnson, Sanofi and Moderna, are scaling up production facilities already. Philanthropist Bill Gates has committed funds to manufacturing facilities for the COVID-19 vaccine worldwide.

Still a long way

Very few vaccines finally make it to the market because of tough regulatory barriers. Regulators around the world have set a high bar for vaccines. Unlike drugs that are used to treat sick people, vaccines are given to healthy individuals to prevent disease. So naturally, regulators demand years of safety data for approval.

The standards set for COVID-19 vaccine are still vague as there is no precedent for such a product. No vaccine has been developed so far against any member of the coronavirus family.

The US FDA has recently made it clear that a vaccine against COVID-19 pandemic would require to be 50% more effective than a placebo and would need to show more evidence than blood tests indicating an immune response. 

In addition, there are concerns about the public acceptance of these “rapid vaccines”. Vaccine sceptics have already expressed strong reservation about these vaccines. Certain anti-vaxxers — groups that press for school vaccine exemptions — have claimed that their membership has skyrocketed since April.

Researchers also warn that if poorly designed and executed, a COVID-19 vaccination could undermine the increasingly tenuous belief in vaccines.

Phase 1/2 data certainly suggests that these vaccines are worth pursuing, even though only phase 3 trials can test how well a vaccine works. 

Experts, however, warn that promoting inconclusive results may actually undermine more immediate public health efforts to control the virus, such as wearing masks and social distancing.

They point out that it looks like a miracle is around the corner, but a vaccine is unlikely to turn out to be a quick fix for the pandemic. 

As Prof Sarah Gilbert of Oxford, who leads the development of the university’s experimental COVID-19 vaccine said: “There is still a long way to go.”