Virus World

IMPORTANCE

In comparing breakthrough infections from the SARS-CoV-2 Delta and Omicron variants, the latter, though milder than Delta infections, were associated with lower antibody titers and limited cross-neutralizing immunity, suggesting reduced protection against re-infection or infection from a future variant.

Summary

Virus-like particle (VLP) and live virus assays were used to investigate neutralizing immunity against Delta and Omicron SARS-CoV-2 variants in 259 samples from 128 vaccinated individuals. Following Delta breakthrough infection, titers against WT rose 57-fold and 3.1-fold compared to uninfected boosted and unboosted individuals, respectively, versus only a 5.8-fold increase and 3.1-fold decrease for Omicron breakthrough infection. Among immunocompetent, unboosted patients, Delta breakthrough infections induced 10.8-fold higher titers against WT compared to Omicron (p=0.037). Decreased antibody responses in Omicron breakthrough infections relative to Delta were potentially related to a higher proportion of asymptomatic or mild breakthrough infections (55.0% versus 28.6%, respectively), which exhibited 12.3-fold lower titers against WT compared to moderate-severe infections (p=0.020). Following either Delta or Omicron breakthrough infection, limited variant-specific cross-neutralizing immunity was observed. These results suggest that Omicron breakthrough infections are less immunogenic than Delta, thus providing reduced protection against reinfection or infection from future variants.

Highlights

1. In breakthrough infections, variant-specific cross-neutralizing immunity is limited.

2. Higher antibody titers are observed in severe versus mild breakthrough infections.

3. Delta breakthroughs exhibited 10.8X higher antibody titers compared to Omicron.

4. The rise in antibody titers from Omicron breakthroughs was 1/3 of that from boosting.

Published in Cell (March 17, 2022):

https://doi.org/10.1016/j.cell.2022.03.019

It’s not yet clear whether the antibody levels produced will lead to immunity to the virus. To prove that, the companies will need to conduct large studies. An experimental Covid-19 vaccine being developed by the drug giant Pfizer and the biotech firm BioNTech spurred immune responses in healthy patients, but also caused fever and other side effects, especially at higher doses. The first clinical data on the vaccine were disclosed Wednesday in a paper released on medRXiv, a preprint server, meaning it has not yet been peer-reviewed or published in a journal. “We still have a ways to go and we’re testing other candidates as well,” said Philip Dormitzer, the chief scientific officer for viral vaccines at Pfizer’s research laboratories. “However, what we can say at this point is there is a viable candidate based on immunogenicity and early tolerability safety data.” 

The study randomly assigned 45 patients to get one of three doses of the vaccine or placebo. Twelve received a 10-microgram dose, 12 a 30-microgram dose, 12 a 100-microgram dose, and nine a placebo. The 100-microgram dose caused fevers in half of patients; a second dose was not given at that level. Following a second injection three weeks later of the other doses, 8.3% of the participants in the 10-microgram group and 75% of those in the 30-microgram group developed fevers. More than 50% of the patients who received one of those doses reported some kind of adverse event, including fever and sleep disturbances. None of these side effects was deemed serious, meaning they did not result in hospitalization or disability and were not life-threatening.

The vaccine generated antibodies against SARS-CoV-2, the virus that causes Covid-19, and some of these antibodies were neutralizing, meaning that they appear to prevent the virus from functioning. Levels of neutralizing antibodies were 1.8 to 2.8 times the level of that in the recovered patients. It’s not certain that higher antibody levels will lead to immunity to the virus. To prove that, Pfizer will need to conduct large studies that aim to prove that people who have received the vaccine are at least 50% less likely to become infected. Those studies are expected to begin this summer, mostly in the United States. Pfizer and BioNTech are testing four different versions of the vaccine, but only one will advance to larger studies....

Preprint available at medRxiv (July 1, 2020):

https://doi.org/10.1101/2020.06.30.20142570

Scientists in Shanghai say some recovered patients show no signs of the neutralising proteins.  Researchers in Shanghai hope to determine whether some recovered coronavirus patients  have a higher risk of reinfection after finding surprisingly low levels of Covid-19 antibodies in a number of people discharged from hospital. A team from Fudan University analysed blood samples from 175 patients discharged from the Shanghai Public Health Clinical Centre and found that nearly a third had unexpectedly low levels of antibodies. In some cases, antibodies could not be detected at all. 

COVID-19 vaccines have recently been updated with the spike protein of SARS-Co-V-2 XBB.1.5 subvariant alone, but their immunogenicity in humans has yet to be fully evaluated and reported, particularly against emergent viruses that are rapidly expanding. We now report that administration of an updated monovalent mRNA vaccine (XBB.1.5 MV) to uninfected individuals boosted serum virus-neutralization antibodies significantly against not only XBB.1.5 (27.0-fold) and the currently dominant EG.5.1 (27.6-fold) but also key emergent viruses like HV.1, HK.3, JD.1.1, and JN.1 (13.3-to-27.4-fold). In individuals previously infected by an Omicron subvariant, serum neutralizing titers were boosted to highest levels (1,764-to-22,978) against all viral variants tested. While immunological imprinting was still evident with the updated vaccines, it was not nearly as severe as the previously authorized bivalent BA.5 vaccine. Our findings strongly support the official recommendation to widely apply the updated COVID-19 vaccines to further protect the public.

Preprint in bioRxiv (Nov. 27, 2023): 

 https://doi.org/10.1101/2023.11.26.568730 

In this study, by characterizing several human monoclonal antibodies (mAbs) isolated from single B cells of the COVID-19–recovered individuals in India who experienced ancestral Wuhan strain (WA.1) of SARS-CoV-2 during early stages of the pandemic, we found a receptor binding domain (RBD)–specific mAb 002-S21F2 that has rare gene usage and potently neutralized live viral isolates of SARS-CoV-2 variants including Alpha, Beta, Gamma, Delta, and Omicron sublineages (BA.1, BA.2, BA.2.12.1, BA.4, and BA.5) with IC50 ranging from 0.02 to 0.13 μg/ml. Structural studies of 002-S21F2 in complex with spike trimers of Omicron and WA.1 showed that it targets a conformationally conserved epitope on the outer face of RBD (class 3 surface) outside the ACE2-binding motif, thereby providing a mechanistic insights for its broad neutralization activity. The discovery of 002-S21F2 and the broadly neutralizing epitope it targets have timely implications for developing a broad range of therapeutic and vaccine interventions against SARS-CoV-2 variants including Omicron sublineages.

Published in Science Advances (October 5, 2022):

https://doi.org/10.1126/sciadv.add2032 

Antibody (Ab) responses to SARS-CoV-2 can be detected in most infected individuals 10-15 days following the onset of COVID-19 symptoms. However, due to the recent emergence of this virus in the human population it is not yet known how long these Ab responses will be maintained or whether they will provide protection from re-infection. Using sequential serum samples collected up to 94 days post onset of symptoms (POS) from 65 RT-qPCR confirmed SARS-CoV-2-infected individuals, we show seroconversion in >95% of cases and neutralizing antibody (nAb) responses when sampled beyond 8 days POS.

We demonstrate that the magnitude of the nAb response is dependent upon the disease severity, but this does not affect the kinetics of the nAb response. Declining nAb titres were observed during the follow up period. Whilst some individuals with high peak ID50 (>10,000) maintained titres >1,000 at >60 days POS, some with lower peak ID50 had titres approaching baseline within the follow up period. A similar decline in nAb titres was also observed in a cohort of seropositive healthcare workers from Guy′s and St Thomas′ Hospitals. We suggest that this transient nAb response is a feature shared by both a SARS-CoV-2 infection that causes low disease severity and the circulating seasonal coronaviruses that are associated with common colds.

This study has important implications when considering widespread serological testing, Ab protection against re-infection with SARS-CoV-2 and the durability of vaccine protection.

Preprint available  at medRxiv  (July 11, 2020):

https://www.medrxiv.org/content/10.1101/2020.07.09.20148429v1

The vaccine from Inovio Pharmaceuticals is designed to work by injecting synthetic DNA that codes for protective antibodies. novio Pharmaceuticals on Tuesday said that its investigational Covid-19 vaccine had “positive” results in a small trial. But the company, which has gained more than $4 billion in value since the coronavirus pandemic began, provided none of the details necessary to determine whether the vaccine is working. In a press release, Inovio said its vaccine led to “immunological response rates” in 34 of 36 patients in the trial, but did not disclose how many patients produced antibodies that neutralize the coronavirus — data key to determining whether the vaccine could protect against infection. The company did not immediately respond to a request for more information. The company’s press release appeared to play down the importance of neutralizing antibodies, pointing to a study that found roughly one-third of patients who recovered from Covid-19 had no detectable antibodies in their blood.

Kathryn Edwards, scientific director of the Vanderbilt Vaccine Research Program in Nashville, Tenn., said Inovio’s vaccine appears to be safe enough to merit further study, but without more data on patient responses, it’s impossible to say whether it might have any beneficial effect. Inovio was early to announce plans to develop a vaccine against the novel coronavirus, boosting its stock price tenfold before producing any clinical data. Its enterprise value started the year at $300 million but grew to $4.5 billion on the hope that its coronavirus vaccine work would lead to a successful product. The stock fell 13% to $27.50 in early Tuesday trading following the release of the early vaccine results.

Press Release available (June 30, 2020):

http://ir.inovio.com/news-releases/news-releases-details/2020/INOVIO-Announces-Positive-Interim-Phase-1-Data-For-INO-4800-Vaccine-for-COVID-19/default.aspx

A collaborative team of scientists has made a successful proof-of-principle demonstration of an advanced HIV vaccine strategy--an approach that may also work in protecting people from an array of other deadly infectious diseases. The team, led by scientists at Scripps Research, also included the Ragon Institute of Massachusetts General Hospital, MIT and Harvard University; the La Jolla Institute for Immunology; and IAVI, a scientific research organization focused on HIV and other global health challenges. Their research appears in Science. The new vaccine strategy centers on stimulating the immune system to produce broadly neutralizing antibodies (bnAbs) against HIV. These special antibodies are capable of neutralizing many different strains of the fast-mutating virus by binding to important yet difficult-to-access regions of the virus surface that don't vary much from strain to strain.

The new vaccine strategy centers on stimulating the immune system to produce broadly neutralizing antibodies (bnAbs) against HIV. These special antibodies are capable of neutralizing many different strains of the fast-mutating virus by binding to important yet difficult-to-access regions of the virus surface that don't vary much from strain to strain. A vaccine that elicits such antibodies could save many millions of lives and billions of dollars--and ultimately, may help eliminate HIV as a significant public health problem. Based on a concept called "germline targeting," this novel strategy could potentially provide protection against the millions of different strains of the virus circulating globally. Achieving this goal has so far been elusive; no HIV vaccine candidate has ever been shown to induce a protective bnAb response in humans.

"I believe that we need a germline-targeting strategy to develop an effective vaccine against HIV, and the same type of strategy may be helpful for making vaccines against many other difficult pathogens," says the study's co-senior author William Schief, PhD, a professor in the Department of Immunology and Microbiology at Scripps Research. "Here, with a great collaborative effort among multiple labs, we've shown the feasibility of a general germline-targeting approach."  This study drew scientists from diverse backgrounds and areas of expertise: co-senior authors are Scripps Research's Schief, Facundo Batista, PhD, chief scientific officer at the Ragon Institute, and Shane Crotty, PhD, a professor in the Vaccine Discovery Division at La Jolla Institute for Immunology.

The germline-targeting approach is meant to launch the production of a desired bnAb by stimulating the right antibody-producing cells. Antibodies are produced by immune cells called B cells, which start out in a "naïve" or "germline" state.  A large repertoire of these germline B cells circulates in the blood and other tissues. In a viral infection--or after immunization with a vaccine that mimics an infecting virus--some germline B cells will bind at least weakly to structures on the surface of the virus. That will stimulate the cells to begin a weeks-long maturation process, in which the antibodies continuously improve in their ability to bind to the surface, thereby neutralizing the virus.  The germline-targeting strategy for an HIV vaccine aims to stimulate the small number of germline B cells that are capable of maturing into cells that make bnAbs. Researchers suspect that other attempts to create an HIV vaccine that elicits bnAbs have failed because they haven't stimulated a sufficient number of these "bnAb precursor" germline B cells. Schief and colleagues previously demonstrated a germline-targeting strategy for one special case: a bnAb that grabs hold of HIV in an unusual way. The new approach is more powerful because it works for antibodies that grip their targets via a much more common mechanism. Furthermore, analyses performed in the study indicate that the approach can likely also be applied to vaccines for many other difficult pathogens such as influenza, dengue virus, Zika virus, hepatitis C and malaria.

To demonstrate the feasibility of their strategy, Schief and Jon Steichen, PhD, a study co-first author and senior scientist in the Schief lab, started by choosing a known HIV bnAb called BG18 as the test case. Informed by structural studies of BG18 bound to its target on the virus--including structures determined for this study in the lab of Andrew Ward, PhD, professor of Integrative Structural and Computational Biology at Scripps Research, and published structures from the lab of Pamela Bjorkman, PhD, at Caltech--Steichen and Schief identified key features of this antibody's HIV-gripping ability.  Next, they searched a large database of human antibody genes in order to find B cells making antibodies that naturally share BG18's key features. Then they used a sophisticated strategy to select and evolve a set of virus-mimicking proteins that could potentially activate multiple BG18-like B cells. These proteins would eventually serve as "immunogens" to stimulate BG18-like B cells in human vaccination.

"As the repertoire of B cells differs from person to person, and in the same person over time, we believe that you need to target more than a few of these cells to have a reasonable chance of activating one of them in any given vaccine recipient," Steichen says.  In the lab of Shane Crotty at the La Jolla Institute for Immunology, tests of blood samples from HIV-negative human donors confirmed that the team's immunogens bound well to normal circulating B cells that have the desired BG18-like features.....

Published in Science (October 31, 2019):

https://doi.org/10.1126/science.aax4380