Vaccine Breakthrough: How India Developed the World’s First DIVA-Compatible Lumpy Skin Disease Vaccine

In 2019, India faced outbreaks of two significant animal diseases: lumpy skin disease (LSD) in cattle and African swine fever (ASF) in pigs. This coincided with the emergence of the novel coronavirus pandemic that would soon engulf the world. Historically, LSD and ASF were endemic to Africa until the early 1990s. From there, they spread to Israel, Egypt, the Middle East, Eastern Europe, and eventually the Indian subcontinent in 2019. Both diseases dominated discussions throughout 2019, until their presence was confirmed in December 2019 and officially reported to the World Organisation for Animal Health (WOAH, formerly OIE).

Our journey to this historical work started from a general objective of enriching our Virus Repository at NRCE (National Research Centre on Equines)/National Centre for Veterinary Type Cultures (NCVTC), Hisar, with yet another new virus. Following my several telephonic discussions with my contacts in various eastern states, we found disease symptoms akin to LSD in cattle farms in and around Ranchi as reported by Professor MK Gupta, Dean of Veterinary Faculty, Bihar Agricultural University, Ranchi Jharkhand. I (BNT), being the director was determined to enrich our Virus Repository by new virus isolates and characterise them further for their application in the development of diagnostics and prophylactics in India. 

I sent a team of experts led by Dr Naveen Kumar (NK, co-author) to Ranchi. On December 23, 2019, the team arrived and examined the affected cattle, quickly identifying symptoms matching lumpy skin disease, and biological samples were collected for further analysis.

Back in Hisar, NK worked tirelessly to identify the virus. PCR (polymerase chain reaction) testing confirmed the presence of the LSD virus (LSDV), marking a major breakthrough. The next challenge was isolating the virus — a complex task requiring meticulous in vitro cultivation. The successful isolation of the LSDV in primary goat kidney cells within 10 days from the Ranchi outbreak proved to be a turning point. A whole genome sequencing revealed that the Indian strain of LSDV was closely related to the Kenyan-type strain. 

The isolation of the LSDV marked the beginning of a new chapter in the country’s fight against LSD, one that would ultimately lead to a homegrown solution to combat the virus spreading across the nation.

Lumpi-ProVacInd: A Landmark achievement
Our discussion on various vaccine options available globally led to a pivotal question: “Can we develop something in our facility?” The next day, NK presented comprehensive information on vaccine options, including live attenuated vaccines, which are considered optimal for poxviral diseases. We decided to pursue virus attenuation.

As the COVID-19 pandemic unfolded, shuttering laboratories worldwide, NK remained resolute in his pursuit of a solution to India's growing LSD crisis. While the world came to a standstill due to COVID-19, LSD continued to spread unchecked, gradually covering the country in its entirety.

As a veterinary pathologist, I foresaw the devastating impact of LSD on India's livestock and economy. Recognizing the nation's vulnerability to transboundary diseases, I knew India needed a homegrown vaccine solution. We opted to attenuate the virus, prioritizing a vaccine candidate. NK and his team persevered, even during the COVID-19 pandemic. After 50 passages in Vero cells over 14 months, genome sequencing revealed mutations characteristic of attenuated LSD strains, along with a critical 801-bp deletion in the ITR region, indicating the virus's attenuation and vaccine potential. By mid-2021, we had an attenuated LSD virus, potentially a vaccine candidate.

As deputy director general, my primary responsibility was to expedite the development of an effective vaccine to combat lumpy skin disease. I convened a meeting with directors of IVRI, NRCE, and NIHSAD to assess their progress. After evaluation, we determined that NK's team was ahead, and opted to test their vaccine at IVRI's Mukteshwar campus. The vaccine demonstrated safety, immunogenicity, and efficacy under controlled conditions, with no risk of reversion to virulence or transmission through bodily secretions.

Field trials with over 26,000 cattle and buffaloes further confirmed the vaccine’s safety and efficacy, including in pregnant and lactating animals. Unlike other Neethling-based vaccines, which often caused adverse reactions like fever or reduced milk yield, Lumpi-ProVacInd showed no such side effects, making it the safest vaccine available for LSD.

The vaccine technology was officially released by central ministers of agriculture and fisheries, animal husbandry, and dairying, after approval from the Director General of ICAR on  August 10, 2022. The vaccine garnered widespread acclaim, prompting nationwide demand. However, the rapid development of a live attenuated vaccine within two years sparked scrutiny. We addressed concerns regarding efficacy and protection, while intensifying our research. This led to breakthroughs, including a PCR test to differentiate vaccine and field strains, a DIVA (differentiating infected from vaccinated animals) test, and deeper insight into protection mechanisms and immune biomarkers.

Science Behind India’s First DIVA-Compatible Vaccine
The development of a DIVA-compatible vaccine for lumpy skin disease is a significant milestone. Mass vaccination is crucial to combat LSD, but current vaccines do not distinguish between infected and vaccinated animals, hindering effective disease management. India's LSD vaccine has a unique genetic deletion, making it distinguishable from natural strains. We have developed an ELISA test using recombinant ORF154 to differentiate the infected from vaccinated cattle on serological basis. This DIVA-compatible vaccine is a groundbreaking achievement in veterinary science.

Pioneering Research on LSDV at NRCE
NK and his team have made groundbreaking contribution to the lumpy skin disease research. Their efforts further provided profound insights into the LSD virus's replication mechanisms, illuminating key molecular pathways. This work has elucidated the pathogenesis of LSDV, aiding targeted therapeutics development. The team led by NK at NRCE, Hisar has also identified novel biomarkers for early diagnosis and defined correlates of vaccine-induced protection. These findings have significantly contributed to vaccine optimization and efficacy assessments, fortifying India's and global efforts to control LSD in cattle.

LSD poses a major threat to dairy productivity, affecting millions of small-scale farmers and the rural economy. The 2022 outbreak saw morbidity rates reach 80 percent and case fatality rates of 67 percent across several states, resulting in an estimated economic loss of Rs. 18,337.76 crore and up to 25 percent decline in milk production. 

Experimental and field data suggest that goatpox vaccine, approved by the government for LSD, provides only partial protection; therefore, it cannot be continued. It is high time the government took decision to adopt CDSCO approved live attenuated LSD vaccine sooner than later to avoid fresh outbreaks in native cattle population. A company called Biovet Pvt. Ltd. has already been granted license to manufacture the vaccine. 

(Dr BN Tripathi is Vice Chancellor, Sher-e-Kashmir University of Agricultural Sciences & Technology, Jammu, Former DDG (AS), ICAR & Former Director, ICAR-NRCE Hisar. Dr Naveen Kumar is Director, ICMR-National Institute of Virology, Pune Former Head, National Centre for Veterinary Type Cultures, ICAR-NRCE, Hisar)